Purine derivatives as liver X receptor agonists

ABSTRACT

The invention relates to methods for the treatment or prevention of an LXR mediated disease or condition, including cardiovascular disease and atherosclerosis, novel compounds of formula (I) for use in such methods and pharmaceutical compositions comprising compounds for use in such methods.

This Application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/US03/016016, filed 20 May 2003, which claims priority to U.S. patentapplication Ser. No. 60/389,689, filed Jun. 17, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to Liver X receptors (LXR). Moreparticularly, the present invention relates to compounds useful asagonists for LXR, pharmaceutical formulations comprising such compounds,and therapeutic use of the same.

The orphan nuclear receptors, LXRα and LXRβ (collectively LXR) play arole in the maintenance of cholesterol balance. Peet et al., Curr. Opin.Genet Dev. 8:571-575 (1998). LXR is a transcription factor whichregulates the expression of Cytochrome P450 7A (CYP7A). CYPP7A catalysesa key step in the conversion of cholesterol to bile acid, which processresults in the removal of cholesterol from the liver.

In addition, LXR binds to the ATP Binding Cassette Transporter-1 (ABC1)(also known as ABCA 1) gene and increases expression of the gene toresult in increased ABC1 protein. ABC1 is a membrane bound transportprotein which is involved in the regulation of cholesterol efflux fromextrahepatic cells onto nascent HDL particles. Mutations in the ABC1gene are responsible for genetic diseases that result in the completeabsence or low levels of HDL cholesterol and a concomitant highlyincreased risk of cardiovascular disease. See Brooks-Wilson et al., Nat.Genet. 22:336-345 (1999); Bodzioch et al., Nat. Genet. 22: 347-351(1999); and Rust et al., Nat. Genet. 22:352-355 (1999). ABC1 knockoutmice homozygous for the mutation in the ABC1 gene have virtually noplasma HDL whereas the heterozygotes produce 50% of the HDL of wild typeanimals. See, Orso et al., Nat. Genet. 24:192-196 (2000) and McNeish etal., Proc. Natl. Acad. Sci. USA 97:4245-4250 (2000). ABC1 knockout micealso show increased cholesterol absorption. See, McNeish et al., Proc.Natl. Acad. Sci. USA 97:4245-4250 (2000). Increased expression of ABC1results in increased HDL cholesterol, decreased absorption ofcholesterol, and increased removal of excess cholesterol fromextrahepatic tissues, including macrophages.

Accordingly compounds which function as LXR agonists would be useful inmethods of increasing ABC1 expression, increasing HDL cholesterol andtreating LXR mediated diseases and conditions such as cardiovasculardisease.

SUMMARY OF THE INVENTION

As a first aspect, the present invention provides a method for theprevention or treatment of an LXR mediated disease or condition in amammal. The method comprises administering a therapeutically effectiveamount of a compound of formula (I):

wherein:

-   n is 1, 2, 3, 4, 5;-   each R¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, and nitro;-   R² is a substituent selected from the group consisting of formulas    i, ii, iii, iv, v, vi and vii:

-   each Ring A and Ring B is the same or different and is independently    selected from the group consisting of C₃₋₁₀cycloalkyl,    C₃₋₁₀cycloalkenyl, Ay and Het;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   a and b are each the same or different and are independently 0 or 1;-   p is 0, 1 or 2;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene;-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;-   each R¹¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷,    —R⁸C(O)R⁶, —R⁸—C(O)Ay, —R⁸—C(O)Het, —R⁸CO₂R⁹, —R⁸C(O)N(R⁹)Ay,    —CH-(Ay)₂, —CH-(Het)₂, nitro and cyano; and-   R¹² is selected from the group consisting of H, alkyl, alkenyl, and    alkynyl,    or a pharmaceutically acceptable salt or solvate thereof. The    present invention also provides the use of a compound of formula (I)    or a pharmaceutically acceptable salt or solvate thereof, for the    preparation of a medicament for the prevention or treatment of an    LXR mediated disease or condition in a mammal.

As a second aspect, the present invention also provides a method forincreasing reverse cholesterol transport in a mammal. The methodcomprises administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereof.The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof, for thepreparation of a medicament for increasing reverse cholesterol transportin a mammal.

As a third aspect, the present invention provides a method forinhibiting cholesterol absorption in a mammal. The method comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof, for thepreparation of a medicament for inhibiting cholesterol absorption in amammal.

As a fourth aspect, the present invention provides a method forincreasing HDL-cholesterol in a mammal. The method comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof, for thepreparation of a medicament for increasing HDL-cholesterol in a mammal.

As a fifth aspect, the present invention provides a method fordecreasing LDL-cholesterol in a mammal. The method comprisesadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof, for thepreparation of a medicament for decreasing LDL-cholesterol in a mammal.

As a sixth aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof. In one embodiment, thepharmaceutical composition further comprises a pharamceuticallyacceptable carrier or diluent.

According to a seventh aspect, the present invention provides a compoundof formula (I)

wherein:

-   n is 1, 2, 3, 4, 5;-   each R¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, and nitro;-   R² is a substituent selected from the group consisting of formulas    iv, vi and vii:

-   each Ring A and Ring B is the same or different and is independently    selected from the group consisting of C₃₋₁₀cycloalkyl,    C₃₋₁₀cycloalkenyl, Ay and Het;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   a and b are each the same or different and are independently 0 or 1;-   p is 0, 1 or 2;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene;-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and-   R¹² is selected from the group consisting of H, alkyl, alkenyl, and    alkynyl,    and pharmaceutically acceptable salts and solvates thereof.

As an eighth aspect, the present invention provides a compound offormula (I-A):

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent selected from the group consisting of formulas i    and ii:

-   Ring A is selected from the group consisting of C₃₋₁₀cycloalkyl,    C₃₋₁₀cycloalkenyl, Ay and Het;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   a is 0 or 1;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;    wherein R³ and R⁴ are not both methyl;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene;-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and-   R¹² is selected from the group consisting of H, alkyl, alkenyl, and    alkynyl,    and pharmaceutically acceptable salts and solvates thereof. The    present invention also provides a pharmaceutical composition    comprising such compound of formula (I-A) and methods of using    compounds of formula (I-A) as herein described for compounds of    formula (I) generally.

As a ninth aspect, the present invention provides a compound of formula(I-A):

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent selected from the group consisting of:

-   q is 0, 1, 2 or 3;-   each R¹¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷,    —R⁸C(O)R⁶, —R⁸—C(O)Ay, —R⁸—C(O)Het, —R⁸CO₂R⁹, —R⁸C(O)N(R⁹)Ay,    —CH-(Ay)₂, —CH-(Het)₂, nitro and cyano;-   g is 0, 1 or 2;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy,    wherein when R² is

then R³ and R⁴ are not both methyl;

-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene; and-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and pharmaceutically acceptable salts and solvates thereof. The    present invention also provides a pharmaceutical composition    comprising such compound of formula (I-A) and methods of using    compounds of formula (I-A) as herein described for compounds of    formula (I) generally.

As a tenth aspect, the present invention provides a compound of formula(I-A):

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent of formula (v-a):

-   p is 0, 1 or 2;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene; and-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and pharmaceutically acceptable salts and solvates thereof. The    present invention also provides a pharmaceutical composition    comprising such compound of formula (I-A) and methods of using    compounds of formula (I-A) as herein described for compounds of    formula (I) generally.

As an eleventh aspect, the present invention provides a compoundselected from the group consisting of:

-   7-(2-chloro-6-fluorobenzyl)-1,3-diethyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-ethyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-isopropyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-methoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   methyl    [7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-phenoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   1-butyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-(cyclopropylmethyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-diisopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-cyclopropyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   1-benzyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   3-benzyl-7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-3-isopropyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-phenyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(4-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3,5-dichlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-(2-naphthyl)-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-[3-(trifluoromethyl)phenyl]-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-methoxyphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-cyclohexyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-iodophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylic    acid;-   7-(2-chloro-6-fluorobenzyl)-8-{3-[(4-hydroxypiperidin-1-yl)carbonyl]piperidin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]-N-(4-hydroxybutyl)piperidine-3-carboxamide;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-[4-(3-methoxyphenyl)piperazin-1-yl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-{4-[4-chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;    and pharmaceutically acceptable salts and solvates thereof. The    present invention also provides a pharmaceutical composition    comprising such compound and methods of using such compound as    herein described for compounds of formula (I) generally.

As additional aspects, the present invention provides a compound offormula (I) or (I-A) as herein before defined, for use in therapy; acompound of formula (I) or (I-A) for use in the prevention or treatmentof an LXR mediated disease or condition in a mammal; a compound offormula (I) or (I-A) for use in the prevention or treatment ofcardiovascular disease in a mammal; a compound of formula (I) or (I-A)for use in the prevention or treatment of atherosclerosis in a mammal; acompound of formula (I) or (I-A0 for increasing reverse cholesteroltransport in a mammal; a compound of formula (I) or (I-A) for inhibitingcholesterol absorption in a mammal; a compound of formula (I) or (I-A)for increasing HDL-cholesterol in a mammal; and a compound of formula(I) or (I-A) for decreasing LDL-cholesterol in a mammal.

Further aspects of the present invention are described in thedescription of preferred embodiments, examples, and claims which follow.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 is a table of compounds according to the present invention. Thetable also provides physical characterization data including MH+ andHPLC purity.

FIGS. 2A and 2B are tables reporting the biological activity of certainexemplified compounds. The table reports the LXRα data in pEC50 and as apercent of the control and LXRβ data in pEC50 and as a percent ofcontrol.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Herein references to “compounds of formula (I)” shall mean the compoundsof formula (I) as described, including subsets of the compounds offormula (I) (e.g., compounds of formula (I-A), together with theirpharmaceutically acceptable salts and solvates.

As used herein, the term “alkyl” refers to aliphatic straight orbranched saturated hydrocarbon chains containing 1-8 carbon atoms.Examples of “alkyl” groups as used herein include but are not limited tomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl,hexyl, octyl and the like. The term “alkyl” also refers to halosubstituted alkyl, including trihaloalkyl, such as trifluoromethyl andtrifluoroethyl among others.

The term “alkylene” refers to an alkyl bridge, i.e., the group -alkyl-,wherein alkyl is as defined above.

As used herein, the term “alkenyl” refers to an aliphatic straight orbranched unsaturated hydrocarbon chain containing 2-8 carbon atoms andat least one and up to three carbon-carbon double bonds. Examples of“alkenyl” groups as used herein include but are not limited to ethenyland propenyl. The term “alkenyl” also refers to halo substitutedalkenyl.

The term “alkenylene” refers to an alkenyl bridge, i.e., the group-alkenyl-, wherein alkenyl is as defined above.

As used herein, the term “alkynyl” refers to an aliphatic straight orbranched unsaturated hydrocarbon chain containing 2-8 carbon atoms andat least one and up to three carbon-carbon triple bonds. Examples of“alkynyl” groups as used herein include but are not limited to propynyl.The term “alkynyl” also refers to halo substituted alkynyl.

As used herein, the term “cycloalkyl” refers to a non-aromaticmonocyclic carbocyclic ring and fused bicyclic carbocyclic rings(including spirocycloalkyl) having the specified number of carbon atomsand no carbon-carbon double bonds. “Cycloalkyl” includes by way ofexample cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and bicycloheptane. “Cycloalkyl” also refers to substitutedcycloalkyl wherein the ring bears one or more substituents selected fromthe group consisting of halo, alkyl, alkenyl, —OH, —Oalkyl, —NH₂,—NH(alkyl) and —N(alkyl)₂. As will be appreciated by those skilled inthe art, the number of possible substituents on the cycloalkyl ring willdepend upon the size of ring. In one preferred embodiment, thecycloalkyl is a cyclohexyl which may be substituted as described above.

The term “cycloalkenyl” as used herein refers to a non-aromaticmonocyclic carbocyclic ring and fused bicyclic carbocyclic rings havingthe specified number of carbon atoms and at least one and up to threecarbon-carbon double bonds. “Cycloalkenyl” includes by way of examplecyclobutenyl, cyclopentenyl, cyclohexenyl and bicyclic cycloalkenylgroups such bicyclo(2.2.1)heptene. “Cycloalkenyl” also refers tosubstituted cycloalkenyl wherein the ring bears one or more substituentsselected from the group consisting of halo, alkyl, alkenyl, —OH,—Oalkyl, —NH₂, —NH(alkyl) and —N(alkyl)₂. As will be appreciated bythose skilled in the art, the number of possible substituents on thecycloalkenyl ring will depend upon the size of ring.

The term “aryl” as used herein refers to aromatic carbocyclic groupsselected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.The term “aryl” also refers to substituted aryl wherein the phenyl ornaphthyl ring bears one or more substituents selected from the groupconsisting of halo, alkyl, alkenyl, —OH, —Oalkyl, —NH₂, —NH(alkyl),—N(alkyl)₂, nitro and cyano. As will be appreciated by those skilled inthe art, the number of possible substituents on the aryl ring willdepend upon the size of ring. For example, when the aryl ring is phenyl,the aryl ring may have up to 5 substituents selected from the foregoinglist. One skilled in the art will readily be able to determine themaximum number of possible substituents for a 1-naphthyl or 2-naphthylring. A particular aryl according to the invention is phenyl, which maybe substituted as described above.

The term “heterocycle” refers to a monocyclic saturated or partiallyunsaturated non-aromatic rings and fused bicyclic non-aromaticcarbocyclic rings, having the specified number of members in the ringand being comprised of carbon and 1, 2 or 3 heteroatoms selected from N,O and S. Examples of particular heterocyclic groups include but are notlimited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran,oxetane, thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. The term “heterocycle” also refers tosubstituted heterocycles wherein the heterocyclic ring bears one or moresubstituents selected from the group consisting of halo, alkyl, alkenyl,—OH, —Oalkyl, —NH₂, —NH(alkyl), —N(alkyl)₂, nitro and cyano. As will beappreciated by those skilled in the art, the number of possiblesubstituents on the heterocyclic ring will depend upon the size of ring.There are no restrictions on the positions of the optional substituentsin the heterocycles. Thus, the term encompasses rings having asubstituent attached to the ring through a heteroatom, particularlythrough N. One skilled in the art will readily be able to determine themaximum number and locations of possible substituents for any givenheterocycle. Particular heterocycles according to the include piperidineand piperizine, either of which may be substituted as described above.

The term “heteroaryl” refers to aromatic monocyclic heterocyclic ringsand fused bicyclic rings wherein at least one ring is aromatic, havingthe specified number of members in the ring, and being comprised ofcarbon and 1, 2 or 3 heteroatoms selected from N, O and S. Examples ofparticular heteroaryl groups include, but are not limited to furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, and indazole. The term “heteroaryl” also refersto substituted heteroaryls wherein the heteroaryl ring bears one or moresubstituents selected from the group consisting of halo, alkyl, alkenyl,—OH, —Oalkyl, —NH₂, —NH(alkyl), —N(alkyl)₂, nitro and cyano. As will beappreciated by those skilled in the art, the number of possiblesubstituents on the heteroaryl ring will depend upon the size of ring.There are no restrictions on the positions of the optional substituentsin heteroaryls. Thus, the term encompasses rings having a substituentattached to the ring through a heteroatom. One skilled in the art willreadily be able to determine the maximum number and locations ofpossible substituents for any given heteroaryl. A preferred heteroarylaccording to the invention is pyridine, which may be substituted asdescribed above.

The term “members” (and variants thereof e.g., “membered”) in thecontext of heterocyclic and heteroaryl groups refers to the total atoms,carbon and heteroatoms N, O and/or S, which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and events that do not occur.

The present invention relates to compounds of formula (I):

wherein:

-   n is 1, 2, 3, 4, 5;-   each R¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, and nitro;-   R² is a substituent selected from the group consisting of formulas    i, ii, iii, iv, v, vi and vii:

-   each Ring A and Ring B is the same or different and is independently    selected from the group consisting of C₃₋₁₀cycloalkyl,    C₃₋₁₀cycloalkenyl, Ay and Het;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   a and b are each the same or different and are independently 0 or 1;-   p is 0, 1 or 2;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷ —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene;-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;-   each R¹¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷,    —R⁸C(O)R⁶, —R⁸—C(O)Ay, —R⁸—C(O)Het, —R⁸CO₂R⁹, —R⁸C(O)N(R⁹)Ay,    —CH-(Ay)₂, —CH-(Het)₂, nitro and cyano; and-   R¹² is selected from the group consisting of H, alkyl, alkenyl, and    alkynyl,    and pharmaceutically acceptable salts or solvates thereof.

In one embodiment, the compounds of formula (I) are defined wherein n is1 or 2. In one particular embodiment, the compounds of formula (I) aredefined wherein n is 1. In another particular embodiment, the compoundsof formula (I) are defined wherein n is 2.

R¹ may be located in the ortho, meta and/or para position(s). In oneembodiment, n is 2 and both R¹ groups are in the ortho positions. Inanother embodiment, n is 2 and one R¹ is in the ortho position and theother R¹ is in the para position. In one embodiment, each R¹ is the sameor different and is independently selected from the group consisting ofhalo and alkyl. In one embodiment, each R¹ is the same or different andis halo.

More specifically, in one embodiment, each R¹ is the same or differentand is independently selected from the group consisting of fluoro,chloro, bromo, iodo, methyl, trihalomethyl, ethyl, trihaloethyl, propyl,isopropyl, butyl, isobutyl, t-butyl and nitro, or any subset thereof. Inone particular embodiment, each R¹ is the same or different and isindependently selected from the group consisting of fluoro, chloro,bromo, iodo, methyl, trifluoromethyl, ethyl and nitro, or any subsetthereof. In one particular embodiment, each R¹ is the same or differentand is independently selected from the group consisting of fluoro andchloro. In particular, one embodiment is defined wherein n is 2, each R¹is ortho and one R¹ is fluoro and the other R¹ is chloro.

In one embodiment, the variables n and R¹ are defined such that thebenzyl group in the compound of formula (I) is selected from the groupconsisting of

In one embodiment, the compounds of formula (I) are defined wherein R2is selected from the group consisting of formulas iv, vi and vii:

or any subset thereof.

In one embodiment, R² is a substituent of formula (iv) above. In suchembodiment, each Ring A and Ring B is the same or different and isindependently selected from the group consisting of C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkenyl, Ay and Het, or any subset thereof; Ay is aryl; andHet is a 3-10 membered heterocycle or a 5-10 membered heteroaryl. In oneparticular embodiment, R² is a substituent of formula (iv) and Ring A isa N-containing 3-10 membered heterocycle or a 5-10 membered heteroaryl(i.e., a heterocycle or heteroaryl having at least one N in the ring).In one embodiment R² is a substituent of formula (iv) or (iv-a) and RingA is a 5-6 membered heterocycle or heteroaryl; more particularly aN-containing 5-6 membered heterocycle or heteroaryl. In one particularembodiment, R² is a substituent of formula (iv) or (iv-a) and Ring A isa N-containing 5-6 membered heterocycle.

In another particular embodiment, R² is a substituent of formula (iv)and Ring B is Ay (aryl). In one embodiment, R² is a substituent offormula (iv) or (iv-a) and Ring B is phenyl. Thus, in one particularembodiment, R² is a substituent of formula (iv-a):

wherein all variables are as defined above in connection with compoundsof formula (I).

In one particular embodiment, wherein R² is a substituent of formula(iv) selected from the group consisting of

or any subset thereof, wherein all varibles are as defined above inconnection with compounds of formula (I).

In one embodiment, when R² is a substituent of formula (iv) or (iv-a),R¹² is H or alkyl, or any subset thereof. In one particular embodimentR² is a substituent of formula (iv) or (iv-a), R¹² is H or methyl; moreparticularly H. In one embodiment, R¹² is methyl. In another embodiment,when R² is a substituent of formula (iv) or (iv-a), p is 0 or 1. In oneparticular embodiment, when R² is a substituent of formula (iv) or(iv-a), p is 0.

In one embodiment, when R² is a substituent of formula (iv) or (iv-a)and b is 1. In one embodiment wherein b is 1, R⁸ is alkylene, moreparticularly C₁₋₃ alkylene.

In another embodiment, when R² is a substituent of formula (iv) or(iv-a), q is 0 or 1. In one particular embodiment, when R² is asubstituent of formula (iv) or (iv-a), q is 1.

In another embodiment, the compounds of formula (I) are defined whereinR² is a substituent of formula (vi):

In one embodiment, R² is a substituent of formula (vi) and Ring A is aHet; more particularly Het bonded to the purine through N. In oneembodiment, when R² is a substituent of formula (vi), Ring A is a 5-6membered heterocycle bonded to the purine through N. In one particularembodiment, R² is a substituent of formula (vi-a):

where Y is N or CH and all other variables are as defined in connectionwith compounds of formula (I).

In one embodiment wherein R² is a substituent of formula (vi) or (vi-a),Ring B is selected from the group consisting of C₃₋₁₀cycloalkyl, 3-10membered heterocycle or 5-10 membered heteroaryl, or any subset thereof.In one particular embodiment R² is a substituent of formula (vi) or(vi-a) and Ring B is selected from the group consisting ofC₅₋₆cycloalkyl or a 5-6 membered heterocycle or heteroaryl, or anysubset thereof. More specifically, in one embodiment, R² is asubstituent of formula (vi) or (vi-a) selected from the group consistingof

or any subset thereof.

In another embodiment, when R² is a substituent of formula (vi) or(vi-a), p is 0 or 1. In one particular embodiment, when R² is asubstituent of formula (vi) or (vi-a), p is 0.

In one embodiment, when R² is a substituent of formula (vi) or (vi-a)and b is 0. In one embodiment wherein b is 1, R⁸ is alkylene, moreparticularly C₁₋₃alkylene. In another embodiment, when R² is asubstituent of formula (vi) or (vi-a), q is 0, 1 or 2. In one particularembodiment, when R² is a substituent of formula (vi) or (vi-a), q is 1.In another particular embodiment, when R² is a substituent of formula(vi) or (vi-a), q is 0.

In another embodiment, the compounds of formula (I) are defined whereinR² is a sustituent of formula (vii):

In one embodiment, R² is a substituent of formula (vii) and Ring A isHet; more particularly Het bonded to the purine through N. In oneembodiment, when R² is a substituent of formula (vii), Ring A is a 5-6membered heterocycle bonded to the purine through N. In one particularembodiment, R² is a substituent of formula (vii-a):

where all variables are as defined in connection with compounds offormula (I).

In one embodiment wherein R² is a substituent of formula (vii) or(vii-a), Ring B is selected from the group consisting ofC₃₋₁₀cycloalkyl, 3-10 membered heterocycle and 5-10 membered heteroaryl,or any subset thereof. In one particular embodiment R² is a substituentof formula (vii) or (vii-a) and Ring B is selected from the groupconsisting of a C₃₋₆cycloalkyl and 5-6 membered heterocycle orheteroaryl, or any subset thereof.

More specifically, in one embodiment, R² is a substituent of formula(vii) or (vii-a) selected from the group consisting of:

or any subset thereof.

In another embodiment, when R² is a substituent of formula (vii) or(vii-a), p is 0 or 1. In one particular embodiment, when R² is asubstituent of formula (vii) or (vii-a), p is 0.

In one embodiment, when R² is a substituent of formula (vii) or (vii-a)and b is 0. In one embodiment wherein b is 1, R⁸ is alkylene, moreparticularly C₁₋₃ alkylene.

In another embodiment, when R² is a substituent of formula (vii) or(vii-a), q is 0 or 1. In one particular embodiment, when R² is asubstituent of formula (vii) or (vii-a), q is 1. In another particularembodiment, when R² is a substituent of formula (vii) or (vii-a), q is0.

In one embodiment of the present invention wherein the compounds offormula (I) are defined such that R² is a substituent of formula (iv),(iv-a), (vi), (vi-a), (vii) or (vii-a), and at least one of p and q isnot 0, each R⁵ is the same or different and is independently selectedfrom the group consisting of halo, alkyl, —OR⁶, —C═O, —C(O)R⁶,—C(O)NR⁶R⁷, —CO₂R⁹, —N(R⁶)C(O)R⁶, —R⁸OR⁶ and nitro, or any subsetthereof. More particular, each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁶,—C(O)NR⁶R⁷ and —CO₂R⁹, or any subset thereof.

More specifically, in one embodiment, each R⁵ is the same or differentand is independently selected from the group consisting of halo, alkyl,—OH, —O-alkyl, —C(O)alkyl, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂,—CO₂H, —NHC(O)alkyl, —R⁸Oalkyl, and nitro, or any subset thereof. Moreparticularly, each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OH, —O-alkyl,—C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂ and —CO₂H, or any subsetthereof.

In one embodiment of the present invention wherein the compounds offormula (I) are defined such that R² is a substituent of formuls (iv),(iv-a), (vi), (vi-a), (vii) or (vii-a), R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof H, alkyl (including halo-substituted alkyl, e.g., trifluoroethyl),C₃₋₁₀cycloalkyl, Ay, R⁸-Ay, —R⁸OH, —R⁸Oalkyl, —R⁸Salkyl, —R⁸CO₂H,—R⁸CO₂alkyl, R⁸—O-Ay, —R⁸C(O)NH₂, —R⁸—C₃₋₁₀cycloalkyl,

or any subset thereof. More particularly, R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof alkyl (including halo substituted alkyl, e.g., trifluoroethyl) andC₃₋₅cycloalkyl. In one embodiment, R³ and R⁴ are the same or differentand are each independently alkyl, or any subset thereof. Morespecifically, R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl and cyclopropyl, or any subset thereof.

In one embodiment of the present invention, R⁸ is alkylene, moreparticularly C₁₋₃alkylene.

In one embodiment of the present invention R⁹ and R¹⁰ are each the sameor different and are selected from the group consisting of H and alkyl,or any subset thereof.

In another embodiment of the present invention, the compounds of formula(I) are defined wherein R² is a substituent of formula (i) or (ii):

In one particular embodiment, the present invention provides compoundsof formula (I-A):

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent selected from the group consisting of formulas i    and ii:

-   Ring A is selected from the group consisting of C₃₋₁₀cycloalkyl,    C₃₋₁₀cycloalkenyl, Ay and Het;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   a is 0 or 1;-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene;-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and-   R¹² is selected from the group consisting of H, alkyl, alkenyl, and    alkynyl,    and pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compounds of formula (I) or (I-A) are definedwherein R² is a substituent of formula (i). In a particular embodiment,R² is a substituent of formula (i) and R⁶ and R⁷ of formula (i), are thesame or different and are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, —R⁸OR⁹, —R⁸—CN and —R⁸—CO₂R⁹,or any subset thereof. More particularly, R² is a substituent of formula(i) and R⁶ and R⁷ of formula (i), are the same or different and are eachindependently selected from the group consisting of H, alkyl and —R⁸OR⁹,or any subset thereof.

In one embodiment, the compounds of formula (I) or (I-A) are definedwherein R² is a substituent of formula (ii). In a particular embodiment,R² is a substituent of formula (ii), and R¹² is H or alkyl, or anysubset thereof.

In another particular embodiment, R² is a substituent of formula (ii),and a is 1. In one embodiment wherein R² is a substituent of formula(ii), and a is 1, R⁸ is alkylene; more particularly C₁₋₃alkylene.

In one embodiment the compounds of formula (I) or (I-A) are definedwherein R² is a substituent of formula (ii), and Ring A is selected fromthe group consisting of C₃₋₆cycloalkyl, phenyl, and 5-6 memberedheterocycle or heteroaryl, or any subset thereof; more particularly RingA is selected from the group consisting of C₃₋₆cycloalkyl and phenyl, orany subset thereof. In a particular embodiment, the compounds of formula(I) or (I-A) are defined wherein R² is a substituent of formula (ii),and Ring A is selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, dioxolane, furan andpiperidine, or any subset thereof. More particular, Ring A in formula(ii) is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and phenyl, or any subset thereof.

In another embodiment, when R² is a substituent of formula (ii), q is 0or 1. In one particular embodiment, when R² is a substituent of formula(ii), q is 1. In another particular embodiment, when R² is a substituentof formula (ii), q is 0.

In one embodiment of the present invention wherein the compounds offormula (I) are defined such that R² is a substituent of formula (i) or(ii), and q is 1 or more, each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁶,—C═O, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —N(R⁶)C(O)R⁶, —R⁸OR⁶ and nitro, orany subset thereof. More particular, each R⁵ is the same or differentand is independently selected from the group consisting of halo, alkyl,—OR⁶, —C(O)NR⁶R⁷ and —CO₂R⁹, or any subset thereof.

More specifically, in one embodiment, each R⁵ is the same or differentand is independently selected from the group consisting of halo, alkyl,—OH, —O-alkyl, —C(O)alkyl, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂,—CO₂H, —NHC(O)alkyl, —R⁸Oalkyl, and nitro, or any subset thereof. Moreparticularly, each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OH, —O-alkyl,—C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂ and —CO₂H, or any subsetthereof.

In one embodiment of the present invention wherein the compounds offormula (I) are defined such that R² is a substituent of formula (i) or(ii), R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, alkyl (includinghalo-substituted alkyl such as trifluoroethyl), C₃₋₁₀cycloalkyl, Ay,R⁸-Ay, —R⁸OH, —R⁸Oalkyl, —R⁸Salkyl, —R⁸CO₂H, —R⁸CO₂alkyl, R⁸—O-Ay,—R⁸C(O)NH₂, —R⁸—C₃₋₁₀cycloalkyl,

or any subset thereof. More particularly, R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof alkyl (including halo substituted alkyl, e.g., trifluoroethyl) andC₃₋₅cycloalkyl, or any subset thereof. In one embodiment, R³ and R⁴ arethe same or different and are each independently alkyl. Morespecifically, R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl and cyclopropyl, or any subset thereof. In oneembodiment, R³ and R⁴ are not both methyl.

In one embodiment of the present invention, R⁸ is alkylene, moreparticularly C₁₋₃alkylene.

In one embodiment of the present invention R⁹ and R¹⁰ are each the sameor different and are selected from the group consisting of H and alkyl.

In another embodiment of the present invention, the compounds of formula(I) are defined such that R² is a substituent of formula (iii):

In one embodiment, the compounds of formula (I) are defined wherein R²is a substituent of formula (iii) and Ring A is selected from the groupconsisting of C₃₋₁₀cycloalkyl, phenyl, and Het, or any subset thereof;more particularly, Ring A is selected from the group consisting ofC₃₋₁₀cycloalkyl, phenyl, and Het bonded to the purine ring through N, orany subset thereof.

More specifically, in one embodiment of the present invention, thecompounds of formula (I) are defined wherein R² is a substituent offormula (iii) and Ring A is selected from the group consisting of

or any subset thereof. In one embodiment, R² is selected from the groupconsisting of optionally substituted phenyl and optionally substitutedpiperidine (i.e.,

or any subset thereof.

In one particular embodiment, the present invention provides compoundsof formula (I-A):

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent selected from the group consisting of:

q is 0, 1, 2 or 3;

-   each R¹¹ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁶C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸N R⁶R⁷,    —R⁸C(O)R⁶, —R⁸—C(O)Ay, —R⁸—C(O)Het, —R⁸CO₂R⁹, —R⁸C(O)N(R⁹)Ay,    —CH-(Ay)₂, —CH-(Het)₂, nitro and cyano;-   g is 0, 1 or 2;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy,-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene; and-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compounds of formula (I-A) are defined wherein R²is optionally substituted piperidinyl, i.e.,

In one embodiment, the compounds of formula (I) wherein R² is asubstituent of formula (iii) or the compounds of formula (I-A) (whereinR² is optionally substituted piperidinyl or optionally substitutedphenyl), q is 0, 1 or 2. In a particular embodiment, q is 0 or 1. In oneembodiment q is 1. In one embodiment, q is 0. In one embodiment of thepresent invention wherein the compounds of formula (I) are defined suchthat R² is a substituent of formula (iii) or the compounds of formula(I-A) (wherein R² is optionally substituted piperidinyl or optionallysubstituted phenyl), and q is 1 or more, each R¹¹ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, —OH, —OR⁶, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷,—N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸CO₂R⁹, R⁸C(O)N(R⁹)Ay and nitro, orany subset thereof. In particular, in one embodiment of the presentinvention wherein R² is a substituent of formula (iii) or the compoundsof formula (I-A) (wherein R² is optionally substituted piperidinyl oroptionally substituted phenyl), and R¹¹ is —OR⁶, —OC(O)R⁶, —OR⁸C(O)R⁶,—S(O)_(g)R⁶, —C(O)R⁶, —C(O)NR⁶R⁷, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷or —R⁸C(O)R⁶; R⁶ is not —R⁸OR⁹. More particular, each R¹¹ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, —OR⁶, —C(O)NR⁶R⁷ and —CO₂R⁹, or any subset thereof.

More specifically, in one embodiment of the compounds of formula (I)wherein R² is a substituent of formula (iii) or the compounds of formula(I-A) (wherein R² is optionally substituted piperidinyl or optionallysubstituted phenyl), each R¹¹ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OH,—Oalkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl, —CO₂R⁸-phenyl, —NHC(O)alkyl,—C(O)NHalkyl, —C(O)N(alkyl)₂, —C(O)N(H)R⁸OH, —C(O)N(H)R⁸Oalkyl,—C(O)N(H)R⁸CN, —C(O)N(alkyl)R⁸CN, —C(O)N(alkyl)R⁸NH₂,—C(O)N(alkyl)R⁸N(H)alkyl, —C(O)N(alkyl)R⁸N(alkyl)₂, —R⁸Oalkyl,—R⁸C(O)N(alkyl)phenyl, —R⁸CO₂alkyl, —R⁸NH₂, —R⁸N(H)alkyl, —R⁸N(alkyl)₂,—CH(phenyl)₂ and nitro, or any subset thereof. More particularly, eachR¹¹ is the same or different and is independently selected from thegroup consisting of halo, alkyl, —OH, —O-alkyl, —C(O)alkyl, —C(O)NH₂,—C(O)NH(alkyl), —C(O)N(alkyl)₂, —CO₂H, —NHC(O)alkyl, —R⁸Oalkyl andnitro, or any subset thereof. In a particular embodiment, each R¹¹ isthe same or different and is independently selected from the groupconsisting of halo, alkyl, —OH, —O-alkyl, —C(O)NH₂, —C(O)NH(alkyl),—C(O)N(alkyl)₂ and —CO₂H, or any subset thereof.

In one embodiment of the present invention wherein the compounds offormula (I) wherein R² is a substituent of formula (iii) or thecompounds of formula (I-A) (wherein R² is optionally substitutedpiperidinyl or optionally substituted phenyl) are defined such that R³and R⁴ are the same or different and are each independently selectedfrom the group consisting of H, alkyl (including halo-substituted alkylsuch as trifluoroethyl), C₃₋₁₀cycloalkyl, Ay, R⁸-Ay, —R⁸OH, —R⁸Oalkyl,—R⁸Salkyl, —R⁸CO₂H, —R⁸CO₂alkyl, R⁸—O-Ay, —R⁸C(O)NH₂,—R⁸—C₃₋₁₀cycloalkyl,

or any subset thereof. More particularly, R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof alkyl (including halo substituted alkyl, e.g., trifluoroethyl) andC₃₋₅cycloalkyl, or any subset thereof. In one embodiment, R³ and R⁴ arethe same or different and are each independently alkyl. Morespecifically, R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl and cyclopropyl, or any subset thereof. In oneembodiment when R² is optionally substituted piperidine, R³ and R⁴ arenot both methyl. In one embodiment, when R² is a substituent of formula(iii), R³ and R⁴ are not both methyl.

In one embodiment of the present invention, R⁸ is alkylene, moreparticularly C₁₋₃alkylene.

In one embodiment of the present invention R⁹ and R¹⁰ are each the sameor different and are selected from the group consisting of H and alkyl.

In another embodiment of the present invention, the compounds of formula(I) are defined such that R² is a substituent of formula (v)

In one embodiment, the compounds of formula (I) are defined wherein R²is a substituent of formula (v) and Ring A is Het; more particularly,Ring A is selected from the group consisting of 5-6 membered heterocycleand heteroaryl, or any subset thereof. In one embodiment, Ring A is aN-containing 3-10 membered heterocycle or 5-10 membered heteroaryl, orany subset thereof; more particularly Ring A is a N-containing 5-6membered heterocycle or heteroaryl, or any subset thereof. In aparticular embodiment Ring A is Het bonded to the purine through N. In aparticular embodiment Ring A is 5-6 membered heterocycle or heteroarylbonded to the purine through N. In one embodiment Ring A is piperazine.

In one embodiment, the compounds of formula (I) are defined wherein R²is a substituent of formula (v) and Ring B is selected from the groupconsisting of C₃₋₁₀cycloalkyl, phenyl, 3-10 membered heterocycle and5-10 membered heteroaryl, or any subset thereof; more particularlyC₅₋₆cycloalkyl, phenyl, 5-6 membered heterocycle and 5-6 memberedheteroaryl. In one embodiment, Ring B is Ay, particularly phenyl.

In one embodiment, the compounds of formula (I) are defined wherein R²is a substituent of formula (v) selected from the group consisting of

subset thereof.

In one particular embodiment, the present invention provides compoundsof formula (I-A)

wherein:

-   R¹⁵ is selected from the group consisting of

-   R² is a substituent of formula (v-a):

p is 0, 1 or 2;

-   q is 0, 1, 2 or 3;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶,    —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷,    —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹,    nitro and cyano;-   g is 0, 1 or 2;-   Ay is aryl;-   Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁cycloalkyl,    —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy;-   R⁶ and R⁷ are the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl, alkynyl,    —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹;-   R⁸ is alkylene or alkenylene; and-   R⁹ and R¹⁰ are each the same or different and are each independently    selected from the group consisting of H, alkyl, alkenyl and alkynyl;    and pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compounds of formula (I) wherein R² is asubstituent of formula (v) or the compounds of formula (I-A) (wherein R²is a substituent of formula (v-a)), p is 0

In one embodiment, the compounds of formula (I) wherein R² is asubstituent of formula (v) or the compounds of formula (I-A) (wherein R²is a substituent of formula (v-a)), q is 0, 1 or 2. In a particularembodiment, q is 0 or 1. In one embodiment q is 1. In one embodiment, qis 0.

In one embodiment of the present invention wherein the compounds offormula (I) are defined such that R² is a substituent of formula (v) orthe compounds of formula (I-A) (wherein R² is a substituent of formula(v-a)), and q is 1 or more, each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁶,—C═O, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —N(R⁶)C(O)R⁶, R⁸OR⁶ and nitro, or anysubset thereof. More particular, each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁶,—C(O)NR⁶R⁷ and —CO₂R⁹, or any subset thereof.

More specifically, in one embodiment of the compounds of formula (I)wherein R² is a substituent of formula (v) or the compounds of formula(I-A) (wherein R² is a substituent of formula (v-a)), each R⁵ is thesame or different and is independently selected from the groupconsisting of halo, alkyl, —OH, —O-alkyl, —C(O)alkyl, —C(O)NH₂,—C(O)NH(alkyl), —C(O)N(alkyl)₂, —CO₂H, —NHC(O)alkyl, —R⁸Oalkyl, andnitro, or any subset thereof. More particularly, each R⁵ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, —OH, —O-alkyl, —C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂ and—CO₂H, or any subset thereof.

In one embodiment of the present invention wherein the compounds offormula (I) wherein R² is a substituent of formula (v) or the compoundsof formula (I-A) (wherein R² is a substituent of formula (v-a)) aredefined such that R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of H, alkyl (includinghalo-substituted alkyl such as trifluoroethyl), C₃₋₁₀cycloalkyl, Ay,R⁸-Ay, —R⁸OH, —R⁸Oalkyl, —R⁸Salkyl, —R⁸CO₂H, —R⁸CO₂alkyl, R⁸—O-Ay,—R⁸C(O)NH₂, —R⁸—C₃₋₁₀cycloalkyl,

or any subset thereof. More particularly, R³ and R⁴ are the same ordifferent and are each independently selected from the group consistingof alkyl (including halo substituted alkyl, e.g., trifluoroethyl) andC₃₋₅cycloalkyl, or any subset thereof. In one embodiment, R³ and R⁴ arethe same or different and are each independently alkyl. Morespecifically, R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl and cyclopropyl, or any subset thereof.

In one embodiment when R² is a substituent of formula (v) or (v-a), R³and R⁴ are not both methyl.

In one embodiment of the present invention, R⁸ is alkylene, moreparticularly C₁₋₃alkylene.

In one embodiment of the present invention R⁹ and R¹⁰ are each the sameor different and are selected from the group consisting of H and alkyl.

Specific examples of particular compounds of the present invention areselected from the group consisting of:

-   7-(2-chloro-6-fluorobenzyl)-1,3-diethyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-ethyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-isopropyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-methoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   methyl    [7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-phenoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   1-butyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-(cyclopropylmethyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-diisopropyl-B-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-cyclopropyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione;-   1-benzyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3-propyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   3-benzyl-7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-3-isopropyl-1-methyl-3,7-di    hydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-phenyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(4-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3,5-dichlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-(2-naphthyl)-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-[3-(trifluoromethyl)phenyl]-3,7-dihydro    -1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-methoxyphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-cyclohexyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-(3-iodophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylic    acid;-   7-(2-chloro-6-fluorobenzyl)-8-{3-[(4-hydroxypiperidin-1-yl)carbonyl]piperidin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]-N-(4-hydroxybutyl)piperidine-3-carboxamide;-   7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-[(3-methoxyphenyl)piperazin-1-yl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;-   7-(2-chloro-6-fluorobenzyl)-8-{4-[4-chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;    and pharmaceutically acceptable salts and solvates thereof.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The presentinvention also covers the individual isomers of the compoundsrepresented by formula (I) as mixtures with isomers thereof in which oneor more chiral centers are inverted.

The present invention contemplates and includes all combinations andsubsets of the particular groups defined above.

Suitable pharmaceutically acceptable salts according to the presentinvention will be readily determined by one skilled in the art and willinclude, for example, acid addition salts prepared from inorganic acidssuch as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric,sulphonic, and sulfuric acids, and organic acids such as acetic,benzenesulphonic, benzoic, citric, ethanesulphonic, fumaric, gluconic,glycollic, isothionic, lactic, lactobionic, maleic, malic,methanesulphonic, succinic, p-toluenesulfonic, salicylic, tartaric, andtrifluoroacetic, formic, malonic, naphthalene-2-sulfonic, sulfamic,decanoic, orotic, 1-hydroxy-2-naphthoic, cholic, and pamoic. In oneembodiment, the compounds of formula (I) are in the form of thehydrochloride salt.

When used in medicine, the salts of a compound of formula (I) should bepharmaceutically acceptable, but pharmaceutically unacceptable salts mayconveniently be used to prepare the corresponding free base orpharmaceutically acceptable salts thereof.

As used herein, the term “solvate” is a crystal form containing thecompound of formula (I) or a pharmaceutically acceptable salt thereofand either a stoichiometric or a non-stoichiometric amount of a solvent.Solvents, by way of example, include water, methanol, ethanol, or aceticacid. Hereinafter, reference to a compound of formula (I) is to anyphysical form of that compound, unless a particular form, salt orsolvate thereof is specified.

In one embodiment, the compounds of formula (I) or (I-A) are LXRagonists. As used herein, the term “LXR agonist” refers to compoundswhich achieve at least 50% activation of LXR relative to24(S),25-epoxycholesterol, the appropriate positive control in the HTRFassay described below in the example below. More particularly, thecompounds of this invention achieve 100% activation of LXR in the HTRFassay. In addition, in one embodiment, the compounds of formula (I) willupregulate expression of ABC1. By upregulating expression of ABC1, ismeant that the induction of ABC1 upon treatment of cells with compoundsof formula (I) at a concentration less than or equal to 10 micromolar isgreater than 2 fold greater than in the absence of compounds of formula(I) in the assay described in the Examples below. Thus the compounds offormula (I) are also useful in methods for upregulating expression ofABC1.

The compounds of formula (I) are useful in therapy in mammals,particularly humans. In particular, the compounds of formula (I) isuseful prevention or treatment of an LXR mediated disease or conditionin a mammal, particularly a human. The compounds of formula (I) are alsouseful in the prevention or treatment of cardiovascular disease in amammal, particularly a human. The compounds of formula (I) are useful inthe prevention or treatment of atherosclerosis in a mammal, particularlya human.

The compounds of formula (I) are also useful for the treatment and/orprophylaxis of a disease or condition characterised by neurondegeneration, inflammation in the CNS, injury or impaired plasticity.The invention also provides a method for the promotion of growth and/orrepair of neurons in diseases or conditions characterised by neurondegeneration, inflammation in the CNS, injury or impaired plasticitywhich method comprises the administration of an effective, non-toxic andpharmaceutically acceptable amount of a compound of formula (I).Particular diseases or conditions are characterised by neurondegeneration and inflammation, and thus benefiting from the growthand/or repair of neurons including stroke, Alzheimer's disease,fronto-temporal dementias (tauopathies), peripheral neuropathy,Parkinson's disease, dementia with Lewy bodies, Huntington's disease,amyotrophic lateral sclerosis and multiple sclerosis. Diseases orconditions characterised by neuron degeneration and/or impairedplasticity include psychiatric disorders such as schizophrenia anddepression. Particular diseases or conditions characterised by neuronalinjury include those conditions associated with brain and/or spinal cordinjury, including trauma.

The compounds of formula (I) are useful for the prevention and treatmentof inflammatory conditions mediated by LXR. Inflammatory conditionsinclude those of the lungs, joints, eyes, bowel, skin and periodontaltissue; particularly those inflammatory conditions mediated by LXR.Conditions of the lung include asthma, adult respiratory distresssyndrome, chronic obstructive pulmonary disease, pneumonia bronchitisand cystic fibrosis (which may additionally or alternatively involve thebowel or other tissue(s)). Conditions of the joint include rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions. Inflammatory eye conditions include uveitis(including iritis) and conjunctivitis. Inflammatory bowel conditionsinclude Crohn's disease, ulcerative colitis and distal proctitis. Otherconditions of the gastro intestinal tract include periodontal disease,esophagitis, NSAID—induced gastrointestinal damage, chemotherapy-inducedmucositis, AIDS related diarrhoea and infectious diarrhoea. Skindiseases include those associated with cell proliferation, such aspsoriasis, eczema and dermatitis (whether or not of allergic origin).Inflammatory conditions of the periodontal tissue include periodontaldisease.

The compounds of formula (I) are useful for increasing reversecholesterol transport in a mammal, particularly a human. The compoundsof formula (I) are useful for inhibiting cholesterol absorption in amammal, particularly a human. The compounds of formula (I) are usefulfor increasing HDL-cholesterol in a mammal, particularly a human. Thecompounds of formula (I) are useful for decreasing LDL-cholesterol in amammal, particularly a human.

The present invention provides a method for the treatment or preventionof an LXR mediated disease or condition in a mammal, particularly ahuman. LXR mediated diseases or conditions include but are not limitedto cardiovascular disease including atherosclerosis, arteriosclerosis,hypercholesteremia, and hyperlipidemia. In particular, the compounds offormula (I) are useful in the treatment and prevention of cardiovasculardisease including artherosclerosis and hypercholesteremia. Certaindiseases or conditions characterised by neuron degeneration,inflammation in the CNS, injury or impaired plasticity, includingAlzheimer's disease are also believed to be mediated through LXR and assuch, the present invention provides a method for the treatment orprevention of such diseases or conditions. In addition, inflammatoryconditions are also believed to be mediated by LXR and as such thepresent invention provides a method for the treatment or prevention ofinflammatory conditions, particularly inflammatory conditions mediatedby LXR. The present invention also provides the use of a compound offormula (I) for the preparation of a medicament for the treatment orprevention of an LXR mediated disease or condition. The presentinvention also provides a method for increasing reverse cholesteroltransport in a mammal, particularly a human. The present invention alsoprovides the use of a compound of formula (I) for the preparation of amedicament for increasing reverse cholesterol transport in a mammal,particularly a human. Lipoprotein metabolism is a dynamic processcomprised of production of triglyceride rich particles from the liver(as VLDL), modification of these lipoprotein particles within the plasma(VLDL to IDL to LDL) and clearance of the particles from the plasma,again by the liver. This process provides the transport of triglyceridesand free cholesterol to cells of the body. Reverse cholesterol transportis the proposed mechanism by which peripheral cholesterol is returned tothe liver from extra-hepatic tissue. The process is carried out by HDLcholesterol. The combination of lipoprotein production (VLDL, HDL) fromthe liver, modification of particles (all) within the plasma andsubsequent clearance back to the liver, accounts for the steady statecholesterol concentration of the plasma. Without wishing to be bound byany particular theory, it is currently believed that the compounds offormula (I) increase reverse cholesterol transport by raising the plasmalevel of HDL cholesterol and/or by increasing cholesterol efflux fromthe arteries.

The present invention provides a method for inhibiting cholesterolabsorption in a mammal, particularly a human. The present invention alsoprovides the use of a compound of formula (I) for the preparation of amedicament for inhibiting cholesterol absorption in a mammal,particularly a human.

The present invention provides a method for increasing HDL-cholesterolin a mammal, particularly a human. The present invention also providesthe use of a compound of formula (I) for the preparation of a medicamentfor inhibiting cholesterol absorption in a mammal, particularly a human.

The present invention also provides a method for decreasingLDL-cholesterol in a mammal, particularly a human. The present inventionalso provides the use of a compound of formula (I) for the preparationof a medicament for inhibiting cholesterol absorption in a mammal,particularly a human.

All of the methods of the present invention comprise the step ofadministering a therapeutically effective amount of the compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof. Asused herein, the term “therapeutically effective amount” refers to anamount of the compound of formula (I) which is sufficient to achieve thestated effect. Accordingly, a therapeutically effective amount of acompound of formula (I) used in the method for the prevention ortreatment of LXR mediated diseases or conditions will be an amountsufficient to prevent or treat the LXR mediated disease or condition.Similarly, a therapeutically effective amount of a compound of formula(I) for use in the method of increasing reverse cholesterol transportwill be an amount sufficient to increase reverse cholesterol transport.

The amount of a compound of formula (I) or pharmaceutically acceptablesalt or solvate thereof, which is required to achieve the desiredbiological effect will depend on a number of factors such as the use forwhich it is intended, the means of administration, and the recipient,and will be ultimately at the discretion of the attendant physician orveterinarian. In general, a typical daily dose for the prevention ortreatment of an LXR mediated disease or condition in a human, forinstance, may be expected to lie in the range of from about 0.01 mg/kgto about 100 mg/kg. This dose may be administered as a single unit doseor as several separate unit doses or as a continuous infusion. Similardosages would be applicable for the treatment of other diseases,conditions and therapies including upregulating expression of ABC1,increasing reverse cholesterol transport, inhibiting cholesterolabsorption, increasing HDL-cholesterol and decreasing LDL-cholesterol.

While it is possible that, for use in therapy, a therapeuticallyeffective amount of a compound of formula (I) may be administered as theraw chemical, it is typically presented as the active ingredient of apharmaceutical composition or formulation. Accordingly, the inventionfurther provides a pharmaceutical composition comprising a compound ofthe formula (I). The pharmaceutical composition may further comprise oneor more pharmaceutically acceptable carriers or diluents. The carrier(s)and/or diluent(s) must be acceptable in the sense of being compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. In accordance with another aspect of the inventionthere is also provided a process for the preparation of a pharmaceuticalformulation including admixing a compound of the formula (I) with one ormore pharmaceutically acceptable carriers and/or diluents.

Pharmaceutical formulations may be presented in unit dose formcontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain a therapeutically effective dose of the compoundof formula (I) or a fraction of a therapeutically effective dose suchthat multiple unit dosage forms might be administered at a given time toachieve the desired therapeutically effective dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of active ingredient. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

A compound of formula (I) can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

A compound of formula (I) may also be delivered by the use of monoclonalantibodies as individual carriers to which the compound molecules arecoupled. The compounds may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research,3(6):318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical compositions adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient. Pharmaceutical compositionsadapted for administration by inhalation include fine particle dusts ormists, which may be generated by means of various types of metered, dosepressurised aerosols, nebulizers or insufflators.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

In the above-described methods of treatment and uses, a compound offormula (I) may be employed alone, in combination with one or more othercompounds of formula (I) or in combination with other therapeuticagents. Thus, the present invention also encompasses pharmaceuticalcompositions further comprising one or more therapeutic agents. In oneembodiment, the pharmaceutical compositions further comprise one or morelipid altering compounds. Examples of suitable lipid altering compoundinclude other LXR agonsts (such as derivatives of CDCA); MHG-CoAreductase inhibitors such as statins (atorvastatin, fluvastatin,pravastatin, lovastatin, cerivastatin, and nisvastatin); squaleneepoxidase inhibitors, squalene synthetase inhibitors, bile acid trasportinhibitors (BATi), human peroxisome proliferator activated receptor(PPAR) gamma agonists such as rosiglitazone, troglitazone, andpioglitazone and thiazolidinediones; PPAR alpha agonists such asclofibrate, fenogibrate and gemfibronzil; PPAR dual alpha/gammaagonists; cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib andcelecoxib; thrombin inhibitors; acyl-coenzyme A; cholesterolacyltransferase (ACAT) inhibitors including selective ACAT inhibitors;microsomal trilyceride transfer protein (MTP) inhibitors; probucol,niacin; cholester absorption inhibitors; bile acid sequestrants; LDLreceptor inducers; platelet aggregation inhibitors such as flycoproteinIIb/IIIa fibrinogen receptor antagonists and aspirin; vitamin B6 andpharmaceutically acceptable salts thereof; vitamine B12; folic acid or apharmaceutically acceptable salt or ester thereof; antioxidant viraminssuch as C and E and beta carotene; beta blockers; angiotensin IIantagonists such as losartan; antiotensin converting enzyme inhibitorssuch as enalapril and captopril; calcium channel blockers such asnifedipine and diltiazam; endothelian antagonists; agents other than LXRligands that enhance ABC1 gene expression; and bisphosphonate compoundssuch as alendronate sodium.

The methods and uses employing these combinations may comprise theadministration of the compound of formula (I) and the other therapeuticagent either sequentially in any order or simultaneously in separate orcombined pharmaceutical compositions. When combined in the samecomposition it will be appreciated that the two compounds must be stableand compatible with each other and the other components of thecomposition and may be formulated for administration. When formulatedseparately they may be provided in any convenient formulation, in such amanner as are known for such compounds in the art.

When a compound of formula (I) is used in combination with anothertherapeutic agent, the dose of each compound may differ from that whenthe compound is used alone. Appropriate doses will be readilyappreciated by those skilled in the art. The appropriate dose of thecompound(s) of formula (I) and the other therapeutically active agent(s)and the relative timings of administration will be selected in order toachieve the desired combined therapeutic effect, and are in the withinthe expertise and discretion of the attendent clinician.

Compounds of the invention can be made according to any suitable methodof organic chemistry. According to one method, compounds of formula (I)are prepared using the process depicted in Scheme 1:

wherein all variables are as defined above in connection with thedescription of compounds of formula (I).

In general, the process comprises the steps of:

-   -   a) alkylating a compound of formula (III) with a substituted        benzyl bromide of formula (IV) to prepare a compound of formula        (V); and    -   b) either        -   1) reacting the compound of formula (V) with an amine of            formula —R²; or        -   2) reacting the compound of formula (V) with a boronic acid            of formula R₂—B(OH)₂ in the presence of a palladium            catalyst,            to prepare a compound of formula (I).

Compounds of formula (IV) are commercially available or can be preparedusing conventional techniques known to those skilled in the art.

The compounds of formula (III) are also commercially available. Inaddition, a compound of formula (III) may be prepared by brominating acompound with formula (II) to prepare a compound of formula (III).

The bromination reaction may be carried out using any suitablebrominating agent such as bromine. The reaction may be carried out inthe presence of sodium acetate or acetic anhydride under heat.

The alkylation reaction of the compound of formula (III) with thecompound of formula (IV) is typically carried out in an inert solvent. Asuitable solvent for this reaction is dimethylsulfoxide (DMSO). A base,such as potassium hydroxide or sodium hydroxide may be employed. Thereaction may be heated.

Alternatively, the reaction may be carried out using a base such aspotassium carbonate in a solvent such as dimethylformamide, withheating. In the embodiment wherein R³ and/or R⁴ are H, the compound offormula (V) may be reacted with an alkyl halide of formula R³—X and/orR⁴—X, where X is halo, to prepare a compound of formula (V) wherein R³and R⁴ are other than H, if desired.

The reaction of the compound of formula (V) with the nucleophile offormula —R² can be carried out in any suitable inert solvent, including,for example dimethylsulfoxide. The reaction may be carried out withheating.

The reaction of the cmopound of formula (V) with a boronic acid offormula R²—B(OH)₂ in the presence of a palldium catalyst is typicallycarried out in a suitable solvent, such as, for example toluene andethanol, with heating. A base may also be employed. A suitable base issodium carbonate. Lithium chloride may be added if desired.

In an analogous process, the compounds of formula (I) may be preparedusing the process depicted in Scheme 2

wherein all variables are as defined in connection with the descriptionof compounds of formula (I).

In general, the process comprises the step of reacting a compound offormula (XI) with a benzyl bromide of formula (IV) to produce a compoundof formula (I). The process is carried out in the same manner as for thereaction of a compound of formula (III) with the benzyl bromide offormula (IV).

The compounds of formula (XI) are commercially available or can beprepared using conventional means. In addition, certain compounds offormula (XI) wherein R² is other than cycloalkyl, may be prepared byreacting a compound of formula (III) with 1) a nucleophile of formula—R² wherein R² is other than cycloalkyl (suitable nucloephiles includean amine or substituted amine); or 2) a boronic acid of formulaR₂—B(OH)₂ in the presence of a palladium catalyst These reactions can becarried out in a manner analogous to that described above for thereaction of a compound of formula (V) to prepare a compound of formula(I).

As will be apparent to one skilled in the art based upon a comparison ofthe processes depicted in Schemes 1 and 2 above, the order in which thesteps of the foregoing reactions are carried out is not critical to theinvention and the steps of these reactions may be carried out in anysuitable order according to the knowledge in the art.

Alternatively, a compound of formula (I) may be prepared by the processdepicted in Scheme 3 below.

wherein all variables are as defined in connection with compounds offormula (I) above.

In general, the process comprises the steps of:

a) reacting diphenyl cyanoimidocarbonate with an amine of formula (VI)to prepare a compound of formula (VII);

b) reacting the compound of formula (VII) with an amine of formula —R²to prepare a compound of formula (VIII);

c) alkylating the compound of formula (VII) with methyl bromoacetate inthe presence of base to prepare a compound of formula (IX);

d) reacting a compound of formula (IX) with an isocyanate or, withtriphosgene and an amine of formula NH₂—R⁴ to prepare a compound offormula (X);

e) cyclizating a compound of formula (X) with base to prepare a compoundof formula (I) wherein R³ is H; and

f) optionally alkylating the compound of formula (I) with an alkylhalide of formula R³—X, wherein X is halo, to prepare a compound offormula (I) wherein R³ is other than H.

Step a) of reacting the diphenyl cyanoimidocarbonate with an amine offormula (VI) is typically carried out in a suitable solvent such asmethylene chloride, in the presence of N,N-diisopropylethylamine (DIEA).The diphenyl cyanoimidocar-bonate is commercially available or may beprepared using conventional techniques. The amines of formula (VI) arecommercially available or may be prepared using conventional techniques.

The reaction of the compound of formula (VII) with the amine of formula—R² to prepare a compound of formula (VIII) is typically carried out ina suitable solvent such as acetonitrile, under heating.

The alkylation reaction of the compound of formula (VIII) with methylbromoacetate is carried out in a suitable solvent such asdimethylformamide or tetrahydroformamide at reduced temperature of about0° C. in the presence of sodium hydride. Th base is typcially sodiummethoxide and the reaction with the base may be carried out in methanoland tetrahydrofuran.

The compound of formula (IX) may be reacted with either an isocyanate offormula R⁴NCO or triphosgene and an amine of formula NH₂—R⁴ to prepare acompound of formula (X). The process involving reaction with theisocyanate may be carried out with heating. The reaction withtriphosgene and the amine is typically carried out in a suitable solventsuch as, for example 1,2-dichloroethane. Triethylamine may be employedas a base.

The compound of formula (X) may be cyclized with a base such as sodiummethoxide in a suitable solvent such as methanol, with heating. Thecyclization reaction results in a compound of formula (I) wherein R³ isH.

Optionally, the compound of formula (I) so prepared may be alkylatedwith an alkyl halide of formula R³—X, wherein X is halo, to prepare acompound of formula (I) wherein R³ is other than H. The alkylatingreaction may be carried out in a suitable solvent such asdimethylformamide in the presence of a base such as potassium carbonate.

As will be apparent to those skilled in the art, a compound of formula(I) may be converted to a different compound of formula (I) usingconventional techniques. As an example, a compound of formula (I-A),prepared using any of the foregoing processes, may be converted to acompound of formula (I-B), which may in turn be converted to a compoundof formula (I-C) using the process depicted in Scheme 4 below.

wherein R⁹ in the compound of formula (I-A) is not H and all othervariables are as defined above in connection with the description ofcompounds of formula (I).

In general, the process comprises the steps of:

-   -   a) saponifing a compound of formula (I-A) to produce a compound        with formula (I-B); and    -   b) reacting the compound of formula (I-B) with an amine of        formula H—NR⁶R⁷ and polymer-supported carbodiimide to prepare a        compound of formula (I-C).

The saponification reaction may be carried out using lithium hydroxidein a suitable solvent such as tetrahydrofuran, with heating.

The reaction of the compound of formula (I-B) with the amine andcarbodiimide can be carried out in a suitable solvent such as methylenechloride.

Other general conversion techniques are known in the art forderivatizing an organic compound. Such techniques may be applied to thecompounds of formula (I) for the purposes of converting a compound offormula (I) to a different compound of formula (I), and as such they arecontemplated by the present invention.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way, the presentinvention being defined by the claims.

In the examples, the following terms have the designated meaning:“pRSETa” is a known expression vector available from Invitrogen; “IPTG”means isopropyl β-D- thiogalactopyranoside; “PO₄” means phosphate; “PBS”means phosphate buffered saline; “TBS” means tris-buffered saline; EDTAmeans ethylenediamine tetraacetic acid; “DTT” means dithiothreitol;“FAF-BSA” means fatty-acid free bovine serum albumin; “SRC-1” meanssteroid receptor coactivator 1; “CS” means charcoal stripped; ‘nM’ meansnanomolar; “μM” means micromolar; “mM” means millimolar; “pM” meanspicomolar; “mmol” means millimoles; “g” means grams; “ng” meansnanograms; “mg/ml” means milligram per milliliter; “μL” meansmicroliters; and “mL” means milliliter.

EXAMPLE 1N-(2-chloro-6-fluorobenzyl)-N′-cyanopiperidine-1-carboximidamide

A solution of diphenylcyanocarboimidate (10 g, 42 mmol) in 168 mL CH₂Cl₂was treated with 2-chloro-6-fluorobenzylamine (6.7 g, 42 mmol) anddiisopropylethylamine (7.3 mL, 42 mmol). The reaction mixture wasstirred at room temperature for 24 hr. The solvent was removed byreduced pressure and the remaining white solid was diluted with CH₂Cl₂and H₂O and extracted 3× with CH₂Cl₂. The organic layers were combinedand the solvent removed by reduced pressure yielding a crude whitesolid. This intermediate (12.8 g, 42 mmol) was dissolved in 80 mLacetonitrile and treated with piperidine (6.2 mL, 63 mmol). The reactionwas heated to reflux for 24 hr. The reaction mixture was cooled and thesolvent removed by reduced pressure. The crude product was trituratedwith ether and collected by filtration to yield a white solid (10 g, 82%yield): ¹H NMR (CDCl₃, 400 MHz) 7.28-7.23 (m, 1H), 7.22-7.18 (m, 1H),7.04-6.98 (m, 1H), 4.94-4.85 (m, 1H), 4.68-4.63 (m, 2H), 3.45-3.39 (m,4H), 1.65-1.57 (m, 6H); MS (ESP+) m/e 295 (MH⁺); Analytical CHN.

EXAMPLE 2 Methyl4-amino-1-(2-chloro-6-fluorobenzyl)-2-piperidin-1-yl-1H-imidazole-5-carboxylate

A solution ofN-(2-chloro-6-fluorobenzyl)-N′-cyanopiperidine-1-carboximidamide (8.35g, 28.3 mmol) in 142 mL DMF was cooled to 0° C. and treated in portionswith NaH (1.25 g, 31.2 mmol). The reaction mixture was stirred for 30min at 0° C. and then methylbromoacetate (2.95 mL, 31.2 mmol) was addeddropwise. The reaction was slowly brought to room temperature andstirred for 15 hr. The reaction was quenched with 20 mL saturatedaqueous NH₄Cl and extracted with 50% EtOAc:hexanes. The organic layerswere combined and the solvent was removed by reduced pressure. The crudeproduct was filtered through a large silica plug and rinsed with 50%EtOAc:hexanes to yield 8.83 g (85% yield) of a yellow oil. This oil(8.83 g, 24.1 mmol) was dissolved in 241 mL THF, treated with 0.5 MNaOMe in MeOH (4.8 mL, 2.41 mmol), and stirred for 4 hr. The reactionmixture was filtered through a large silica plug and rinsed with 100%EtOAc. The solvent was removed by reduced pressure affording the titlecompound (7.92 g, 90% yield) as a light yellow solid:): ¹H NMR (CDCl₃,400 MHz) 7.17-7.06 (m, 2H), 6.92-6.86 (m, 1H), 5.23 (s, 2H), 5.14-4.97(m, 2H), 3.61 (s, 3H), 3.14-3.05 (m, 4H), 1.68-1.48 (m, 6H); MS (ESP+)m/e 367 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.34.

EXAMPLE 37-(2-chloro-6-fluorobenzyl)-3-methyl-1-phenyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

In a sealed tube, a solution of methyl4-amino-1-(2-chloro-6-fluorobenzyl)-2-piperidin-1-yl-1H-imidazole-5-carboxylate(150 mg, 0.41 mmol) in xylenes (3.5 mL) was treated with phenylisocyanate (98 □L, 0.90 mmol). The reaction was heated to 140° C. for 3hr. cooled to room temperature, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel cartridge,Biotage, 32-63 □m, 60 Å) with 33% EtOAc:hexanes as the eluent to afford160 mg (80% yield) of the urea intermediate. The urea (150 mg, 0.31mmol) was dissolved in MeOH (3.1 mL) and treated with 0.5 M NaOMe inMeOH (1.36 mL, 0.68 mmol). The reaction was heated to 80° C. and stirredfor 1 hr. The crude product was filtered through a plug of silica andrinsed with 100% EtOAc to yield the cyclized intermediate (83 mg, 59%yield). A solution of this intermediate (20 mg, 0.044 mmol) and K₂CO₃(61 mg, 0.44 mmol) in 880 μL DMF was treated with methyl iodide (14 mL,0.22 mmol). The reaction was stirred at room temperature for 24 hr.filtered through a silica plug, and rinsed with EtOAc. After removal ofthe solvent under reduced pressure, the crude product was purified bypreparative thin layer chromatography (silica gel, 1 mm plate, EMScience 20×20 cm silica gel 60 F₂₆₄) eluting with EtOAc:hexane (1:1) togive 16 mg (76% yield) of the title compound as a white solid: ¹H NMR(CDCl₃, 400 MHz) 7.45-7.39 (m, 2H), 7.38-7.32 (m, 1H), 7.22-7.11 (m,4H), 6.96-6.90 (m, 1H), 5.56 (s, 2H), 3.54 (s, 3H), 3.14-3.01 (m, 4H),1.52-1.46 (m, 6H); MS (ESP+) m/e 468 (MH⁺); TLC (EtOAc:hexanes/1:1)R_(f)=0.15.

EXAMPLE 47-(2-chloro-6-fluorobenzyl)-1,3-diethyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 24 mg (73% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400MHz) 7.21-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.90 (m, 1H), 5.53 (s,2H), 4.08 (q, 2H, J=7.1 Hz), 3.96 (q, 2H, J=7.1 Hz), 3.07-3.01 (m, 4H),1.52-1.46 (m, 6H), 1.29 (t, 3H, J=7.1 Hz), 1.13 (t, 3H, J=7.1 Hz); MS(ESP+) m/e 434 (MH⁺).

EXAMPLE 57-(2-chloro-6-fluorobenzyl)-1-ethyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 23 mg (70% yield) of a pale pink solid: ¹H NMR (CDCl₃, 400 MHz)7.20-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.53 (s, 2H),5.15-5.04 (m, 1H), 3.95 (q, 2H, J=7.1 Hz), 3.07-2.99 (m, 4H), 1.53 (d,6H, J=7.0 Hz), 1.51-1.46 (m, 6H), 1.13 (t, 3H, J=7.1 Hz); MS (ESP+) m/e448 (MH⁺).

EXAMPLE 67-(2-chloro-6-fluorobenzyl)-3-ethyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 19 mg (80% yield) of a yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.20-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.53 (s, 2H),4.07 (q, 2H, J=7.1 Hz), 3.89-3.83 (m, 2H), 3.08-3.00 (m, 4H), 1.62-1.52(m, 2H), 1.52-1.46 (m; 6H), 1.28 (t, 3H, J=7.1 Hz), 0.83 (t, 3H, J=7.4Hz); MS (ESP+) m/e 448 (MH⁺).

EXAMPLE 77-(2-chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 21 mg (86% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.20-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.53 (s, 2H),5.14-5.05 (m, 1H), 3.88-3.81 (m, 2H), 3.06-3.01 (m, 4H), 1.62-1.55 (m,2H), 1.52 (d, 6H, J=6.9 Hz), 1.50-1.46 (m, 6H), 0.84 (t, 3H, J=7.6 Hz);MS (ESP+) m/e 462 (MH⁺).

EXAMPLE 87-(2-chloro-6-fluorobenzyl)-1-isopropyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 11 mg (46% yield) of a pink solid: ¹H NMR (CDCl₃, 400 MHz)7.22-7.14 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.90 (m, 1H), 5.54 (s, 2H),5.23-5.13 (m, 1H), 3.46 (s, 3H), 3.07-2.98 (m, 4H), 1.52-1.45 (m, 6H),1.40 (d, 6H, J=6.9); MS (ESP+) m/e 434 (MH⁺).

EXAMPLE 97-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-methoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 20 mg (88% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.96-6.91 (m, 1H), 5.52 (s, 2H),4.23 (t, 2H, J=6.0 Hz), 3.95 (q, 2H, J=7.1 Hz), 3.70 (t, 2H, J=6.0 Hz),3.35 (s, 3H), 3.07-3.00 (m, 4H), 1.52-1.45 (m, 6H), 1.13 (t, 3H, J=7.1Hz); MS (ESP+) m/e 464 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.45.

EXAMPLE 10 Methyl[7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate

The title compound was prepared according to the procedure of Example 3to give 20 mg (84% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.15 (m, 1H), 7.14-7.10 (m, 1H), 6.97-6.91 (m, 1H), 5.52 (s, 2H),4.75 (s, 2H), 3.96 (q, 2H, J=7.1 Hz), 3.74 (s, 3H), 3.04-3.00 (m, 4H),1.51-1.45 (m, 6H), 1.13 (t, 3H, J=7.1 Hz); MS (ESP+) m/e 478 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.48.

EXAMPLE 117-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-phenoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 23 mg (89% yield) of a pale pink solid: ¹H NMR (CDCl₃, 400 MHz)7.26-7.15 (m, 3H), 7.14-7.10 (m, 1H), 6.98-6.93 (m, 1H), 6.93-6.87 (m,3H), 5.52 (s, 2H), 4.43 (t, 2H, J=6.1 Hz), 4.30 (t, 2H, J=6.1 Hz), 3.96(q, 2H, J=7.1 Hz), 3.07-2.99 (m, 4H), 1.55-1.45 (m, 6H), 1.14 (t, 3H,J=7.1 Hz); MS (ESP+) m/e 527 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.61.

EXAMPLE 127-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-hydroxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 22 mg (99% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.22-7.16 (m, 1H), 7.14-7.11 (m, 1H), 6.98-6.92 (m, 1H), 5.53 (s, 2H),4.32-4.28 (m, 2H), 3.96 (q, 2H, J=7.1 Hz), 3.92-3.88 (m, 2H), 3.08-3.02(m, 4H), 1.51-1.46 (m, 6H), 1.13 (t, 3H, J=7.1 Hz); MS (ESP+) m/e 450(MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.18.

EXAMPLE 137-(2-chloro-6-fluorobenzyl)-3-cyclopentyl-1-ethyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 3to give 11 mg (49% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.97-6.91 (m, 1H), 5.54 (s, 2H),5.28-5.17 (m, 1H), 3.96 (q, 2H, J=7.1 Hz), 3.08-2.99 (m, 4H), 2.28-2.16(m, 2H), 2.04-1.84 (m, 4H), 1.63-1.54 (m, 2H), 1.52-1.45 (m, 6H), 1.14(t, 3H, J=7.1 Hz); MS (ESP+) m/e 474 (MH⁺); TLC (EtOAc:hexanes/1:1)R_(f)=0.68.

EXAMPLE 142-[7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetamide

The title compound was prepared according to the procedure of Example 3to give 17 mg (72% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.22-7.15 (m, 1H), 7.14-7.09 (m, 1H), 6.98-6.90 (m, 1H), 6.11 (s, 1H),5.79 (s, 1H), 5.51 (s, 2H), 4.68 (s, 2H), 3.95 (q, 2H, J=7.1 Hz),3.09-2.99 (m, 4H), 1.52-1.43 (m, 6H), 1.13 (t, 3H, J=7.1 Hz); MS (ESP+)m/e 463 (MH⁺); TLC (MeOH:CH₂Cl₂/1:1) R_(f)=0.45.

EXAMPLE 15 tert-Butyl[7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate

The title compound was prepared according to the procedure of Example 3to give 29 mg (86% yield) of a pale yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.20-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.52 (s, 2H),4.63 (s, 2H), 3.96 (q, 2H, J=7.1 Hz), 3.06-2.96 (m, 4H), 1.51-1.45 (m,6H), 1.42 (s, 9H), 1.13 (t, 3H, J=7.1 Hz); MS (ESP+) m/e 520 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.73.

EXAMPLE 167-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-(3-methoxypropyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

A solution of methyl4-amino-1-(2-chloro-6-fluorobenzyl)-2-piperidin-1-yl-1H-imidazole-5-carboxylate(50 mg, 0.14 mmol) in dichloroethane (1.75 mL) was cooled to 0° C. andtreated with triphosgene (33 mg, 0.11 mmol). The reaction was stirredfor 10 min and triethylamine (41 μL, 0.29 mmol) was pipetted in. Afteran additional 10 min, 3-methoxypropylamine (69 μL, 0.68 mmol) was addedand the reaction was heated to 85° C. for 15 hr. The reaction was cooledto room temperature, filtered through a silica plug, rinsed with EtOAc,and concentrated in vacuo. The crude product was purified by preparativethin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cmsilica gel 60 F₂₆₄) eluting with 30% EtOAc:CH₂Cl₂ to give 30 mg (44%yield) of the intermediate urea. The urea (30 mg, 0.06 mmol) wasdissolved in MeOH (0.6 mL) and treated with 0.5 M NaOMe in MeOH (0.26mL, 0.13 mmol). The reaction was heated to 70° C. and stirred for 15 hr.The crude product was filtered through a plug of silica and rinsed with100% EtOAc to yield the cyclized intermediate. A solution of thisintermediate (28 mg, 0.06 mmol) and K₂CO₃ (83 mg, 0.60 mmol) in 600 μLDMF was treated with isopropyl iodide (29 μL, 0.30 mmol). The reactionwas stirred at room temperature for 24 hr. filtered through a silicaplug, and rinsed with EtOAc. After removal of the solvent under reducedpressure, the crude product was purified by preparative thin layerchromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel60 F₂₆₄) eluting with EtOAc:hexane (1:1) to give 23 mg (78% yield) ofthe title compound as a clear oil: ¹H NMR (CDCl₃, 400 MHz) 7.20-7.14 (m,1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.54 (s, 2H), 5.13-5.05 (m,1H), 3.98 (t, 2H, J=7.1 Hz), 3.35 (t, 2H, J=6.6 Hz), 3.26 (s, 3H),3.05-3.00 (m, 4H), 1.88-1.80 (m, 2H), 1.53 (d, 6H, J=6.9 Hz), 1.50-1.45(m, 6H); MS (ESP+) m/e 492 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.60.

EXAMPLE 17 Methyl3-[7-(2-chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]propanoate

The title compound was prepared according to the procedure of Example 16to give 3 mg (14% yield) of a pale yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.23-7.17 (m, 1H), 7.16-7.12 (m, 1H), 6.99-6.93 (m, 1H), 5.54 (s, 2H),5.15-5.06 (m, 1H), 4.22 (t, 2H, J=7.7 Hz), 3.64 (s, 3H), 3.09-3.03 (m,4H), 2.60 (t, 2H, J=7.7 Hz), 1.57-1.54 (m, 6H), 1.54-1.49 (m, 6H); MS(ESP+) m/e 506 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.61.

EXAMPLE 181-Butyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 17 mg (65% yield) of a pale yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.54 (s, 2H),3.93-3.87 (m, 2H), 3.49 (s, 3H), 3.07-3.02 (m, 4H), 1.54-1.44 (m, 8H),1.19-1.31 (m, 2H), 0.86 (t, 3H, J=7.2 Hz); MS (ESP+) m/e 448 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.72.

EXAMPLE 191-Butyl-7-(2-chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 14 mg (54% yield) of a pale yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.97-6.90 (m, 1H), 5.55 (s, 2H),5.15-5.06 (m, 1H), 3.93-3.84 (m, 2H), 3.08-3.00 (m, 4H), 1.56-1.44 (m,8H), 1.33-1.21 (m, 2H), 0.87 (t, 3H, J=7.2 Hz); MS (ESP+) m/e 476 (MH⁺);TLC (EtOAc:hexanes/1:1) R_(f)=0.88.

EXAMPLE 20 tert-butyl[7-(2-chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]acetate

The title compound was prepared according to the procedure of Example 16to give 10 mg (28% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.20-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.96-6.90 (m, 1H), 5.54 (s, 2H),5.13-5.05 (m, 1H), 4.54 (s, 2H), 3.06-3.01 (m, 4H), 1.53 (d, 6 h, J=7.1Hz), 1.50-1.46 (m, 6H), 1.40 (s, 9H); MS (ESP+) m/e 535 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.66.

EXAMPLE 217-(2-Chloro-6-fluorobenzyl)-3-isopropyl-1-(2-methoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 22 mg (56% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.96-6.90 (m, 1H), 5.55 (s, 2H),5.16-5.04 (m, 1H), 4.14 (t, 2H, J=6.0 Hz), 3.55 (t, 2H, J=6.0 Hz), 3.30(s, 3H), 3.05-2.97 (m, 4H), 1.53 (d, 6H, J=6.9 Hz), 1.51-1.44 (m, 6H);MS (ESP+) m/e 479 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.64.

EXAMPLE 227-(2-Chloro-6-fluorobenzyl)-1-cyclopentyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 17 mg (51% yield) of a yellow solid: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.90 (m, 1H), 5.56 (s, 2H),5.37-5.26 (m, 1H), 5.14-5.05 (m, 1H), 3.06-2.97 (m, 4H), 2.13-2.03 (m,2H), 1.96-1.86 (m, 2H), 1.79-1.69 (m, 2H), 1.57-1.55 (m, 2H), 1.53 (d,6H, J=6.9 Hz), 1.49-1.43 (m, 6H); MS (ESP+) m/e 488 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.85.

EXAMPLE 237-(2-Chloro-6-fluorobenzyl)-1-(2-furyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 9 mg (20% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.29-7.26 (m, 1H), 7.21-7.15 (m, 1H), 7.14-7.10 (m, 1H), 6.98-6.91 (m,1H), 6.25-6.22 (m, 2H), 5.58 (s, 2H), 5.15-5.07 (m, 3H), 3.05-2.99 (m,4H), 1.53 (d, 6H, J=6.9 Hz), 1.49-1.43 (m, 6H); MS (ESP+) m/e 500 (MH⁺);TLC (EtOAc:hexanes/1:1) R_(f)=0.81.

EXAMPLE 247-(2-Chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-thien-2-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 27 mg (66% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.22-7.15 (m, 1H), 7.14-7.08 (m, 3H), 6.98-6.91 (m, 1H), 6.88-6.84 (m,1H), 5.57 (s, 2H), 5.25 (s, 2H), 5.14-5.06 (m, 1H), 3.04-2.98 (m, 4H),1.52 (d, 6H, J=6.9 Hz), 1.49-1.43 (m, 6H); MS (ESP+) m/e 516 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.74.

EXAMPLE 257-(2-Chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 27 mg (67% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.22-7.15 (m, 1H), 7.13-7.10 (m, 1H), 6.97-6.91 (m, 1H), 5.50 (s, 2H),5.15-5.06 (m, 1H), 4.61 (q, 2H, J=8.6 Hz), 3.13-3.05 (m, 4H), 1.57-1.48(m, 12H); MS (ESP+) m/e 502 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.74.

EXAMPLE 267-(2-Chloro-6-fluorobenzyl)-1-isobutyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 24 mg (56% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.19-7.12 (m, 1H), 7.12-7.07 (m, 1H), 6.96-6.89 (m, 1H), 5.52 (s, 2H),5.14-5.04 (m, 1H), 3.73 (d, 2H, J=7.4 Hz), 3.09-3.00 (m, 4H), 2.10-1.96(m, 1H), 1.57-1.44 (m, 12H), 0.79 (d, 6H, J=6.7 Hz); MS (ESP+) m/e 476(MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.88.

EXAMPLE 277-(2-Chloro-6-fluorobenzyl)-1-isopentyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 30 mg (55% yield) of a yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.20-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.89 (m, 1H), 5.57 (s, 2H),5.15-5.05 (m, 1H), 3.96-3.84 (m, 2H), 3.05-2.97 (m, 4H), 1.60-1.55 (m,1H), 1.53 (d, 6H, J=6.9 Hz), 1.48-1.40 (m, 8H), 0.90 (d, 6H, J=6.5 Hz);MS (ESP+) m/e 490 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.91.

EXAMPLE 287-(2-Chloro-6-fluorobenzyl)-3-isopropyl-1-[3-(methylthio)propyl]-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 24 mg (70% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.14-7.09 (m, 1H), 6.97-6.91 (m, 1H), 5.53 (s, 2H),5.13-5.05 (m, 1H), 3.98 (t, 2H, J=7.1 Hz), 3.08-3.01 (m, 4H), 2.45-2.38(m, 2H), 1.90-1.81 (m, 2H), 1.53 (d, 6H, J=6.9 Hz), 1.51-1.47 (m, 6H);MS (ESP+) m/e 508 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.76.

EXAMPLE 297-(2-Chloro-6-fluorobenzyl)-1-(cyclopropylmethyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 19 mg (65% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.21-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.90 (m, 1H), 5.53 (s, 2H),5.15-5.06 (m, 1H), 3.79 (d, 2H, J=7.3 Hz), 3.08-2.99 (m, 4H), 1.54 (d,6H, J=6.9 Hz), 1.52-1.46 (m, 6H), 1.23-1.14 (m, 1H), 0.38-0.26 (m, 4H);MS (ESP+) m/e 474 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.84.

EXAMPLE 307-(2-Chloro-6-fluorobenzyl)-1,3-diisopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 18 mg (49% yield) of a pale yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.13 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.89 (m, 1H), 5.54 (s, 2H),5.22-5.13 (m, 1H), 5.13-5.03 (m, 1H), 3.05-2.98 (m, 4H), 1.52 (d, 6H,J=6.9 Hz), 1.50-1.44 (m, 6H), 1.40 (d, 6H, J=6.9 Hz); MS (ESP+) m/e 462(MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.88.

EXAMPLE 317-(2-Chloro-6-fluorobenzyl)-1-cyclopropyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 16to give 5 mg (20% yield) of a yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.90 (m, 1H), 5.53 (s, 2H),5.11-5.02 (m, 1H), 3.06-2.99 (m, 4H), 2.61-2.54 (m, 1H), 1.52 (d, 6H,J=6.9 Hz), 1.50-1.46 (m, 6H), 1.10-1.04 (m, 2H), 0.67-0.61 (m, 2H); MS(ESP+) m/e 460 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.64.

EXAMPLE 328-Bromo-7-(2-chloro-6-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 3-methyl-8-bromoxanthine (1.5 g, 6.1 mmol, Klein, J. P.PCT Int. Appl. WO 0061583, 2000) and K₂CO₃ (0.84 g, 6.1 mmol) in 6 mLDMF was treated with 2-chloro-6-fluorobenzyl bromide. The reactionmixture was heated to 60° C. for 2 hr, cooled, and poured onto icewater. The solid precipitate was filtered and dried to yield 1.8 g (76%yield) of a white solid: ¹H NMR (DMSO, 400 MHz) 7.43-7.36 (m, 1H),7.34-7.30 (m, 1H), 7.22-7.15 (m, 1H), 5.67 (s, 2H), 3.29 (s, 3H); MS(AP+) m/e 389 (MH⁺).

EXAMPLE 337-(2-chloro-6-fluorobenzyl)-1-ethyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione(200 mg, 0.52 mmol) and K₂CO₃ (357 mg, 2.6 mmol) in 4 mL DMF was treatedwith iodoethane (412 μL, 5.2 mmol). The reaction was heated to 50° C.for 48 hr. The reaction mixture was cooled, diluted with H₂O, andextracted 3× with 50% EtOAc:hexanes. The organic layers were combinedand the solvent removed under reduced pressure (116 mg, 54% yield). Thecrude product (52 mg, 0.13 mmol) was dissolved in 200 μL DMSO andtreated with piperidine (37 μL, 0.38 mmol). The reaction mixture washeated to 100° C. for 15 hr. The reaction mixture was cooled, dilutedwith H₂O, and extracted 3× with 50% EtOAc:hexanes. The organic layerswere combined, dried with Mg₂SO₄, and evaporated under reduced pressure.The crude product was purified by preparative thin layer chromatography(silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F₂₆₄) elutingwith EtOAc:hexane (1:1) to give 31 mg (56% yield) of the title compoundas a white solid: ¹H NMR (CDCl₃, 400 MHz) 7.21-7.14 (m, 1H), 7.13-7.09(m, 1H), 6.96-6.90 (m, 1H), 5.53 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 3.49(s, 3H), 3.09-3.00 (m, 4H), 1.54-1.46 (m, 6H), 1.13 (t, 3H, J=7.0 Hz);MS (ESP+) m/e 420 (MH⁺).

EXAMPLE 347-(2-Chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 33to give 22 mg (51% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400MHz) 7.21-7.14 (m, 1H), 7.13-7.09 (m, 1H), 6.96-6.90 (m, 1H), 5.53 (s,2H), 3.90-3.83 (m, 2H), 3.49 (s, 3H), 3.07-3.02 (m, 4H), 1.62-1.53 (m,2H), 1.52-1.46 (m, 6H), 0.83 (t, 3H, J=7.5 Hz); MS (ESP+) m/e 434 (MH⁺);TLC (EtOAc:CH₂Cl₂/1:9) R_(f)=0.29.

EXAMPLE 351-Benzyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 33to give 125 mg (74% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.32-7.28 (m, 2H), 7.24-7.14 (m, 4H), 7.14-7.10 (m, 1H), 6.98-6.91 (m,1H), 5.55 (s, 2H), 5.09 (s, 2H), 3.47 (s, 3H), 3.09-3.03 (m, 4H),1.53-1.46 (m, 6H); MS (ESP+) m/e 482 (MH⁺); TLC (EtOAc:CH₂Cl₂/1:9)R_(f)=0.36.

EXAMPLE 367-(2-Chloro-6-fluorobenzyl)-1-(3-methoxybenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 33to give 13 mg (29% yield) of a yellow oil: ¹H NMR (CDCl₃, 400 MHz)7.25-7.09 (m, 3H), 6.98-6.85 (m, 3H), 6.75-6.70 (m, 1H), 5.56 (s, 2H),5.08 (s, 2H), 3.74 (s, 3H), 3.48 (s, 3H), 3.10-3.02 (m, 4H), 1.53-1.46(m, 6H); MS (ESP+) m/e 513 (MH⁺); TLC (EtOAc:CH₂Cl₂/1:9) R_(f)=0.28.

EXAMPLE 378-Bromo-7-(2-chloro-6-fluorobenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 1-methylxanthine (1 g, 6 mmol) and sodium acetate (591 mg,7.2 mmol) in 30 mL acetic acid was treated with bromine (371 μL, 7.2mmol). The reaction mixture was heated to 50° C. for 15 hr. Anadditional 246 mg sodium acetate and 155 μL bromine was added and thereaction was heated at 50° C. for another 15 hr. The reaction was cooledand the solids collected by filtration, rinsed with chloroform, anddried under reduced pressure to yield a white solid (1.0 g, 68% yield).A solution of the solid (1.0 g, 4.1 mmol) in 30 mL DMF was heated at 80°C. for 30 min. The reaction mixture was cooled and treated with Na₂CO₃(435 mg, 4.1 mmol) and 2-chloro-6fluorobenzyl bromide (1.0 g, 4.5 mmol)and stirred at room temperature for 15 hr. Upon addition of H₂O, theresulting precipitate was collected by filtration and then trituratedwith EtOAc. The remaining solids were collected by filtration, rinsedwith EtOAc, and dried under reduced pressure to yield 0.69 g (43% yield)of a white solid: ¹H NMR (DMSO, 400 MHz) 12.06 (s, 1H), 7.42-7.35 (m,1H), 7.34-7.30 (m, 1H), 7.21-7.14 (m, 1H), 5.67 (s, 2H), 3.09 (s, 3H);MS (ESP+) m/e 389 (MH⁺).

EXAMPLE 387-(2-Chloro-6-fluorobenzyl)-3-ethyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione(200 mg, 0.52 mmol) and K₂CO₃ (86 mg, 0.62 mmol) in 5.2 mL DMF wastreated with iodoethane (412 μL, 5.2 mmol). The reaction was stirred atroom temperature for 15 hr. The reaction mixture was diluted with H₂O,and extracted 3× with 50% EtOAc:hexanes. The organic layers werecombined and the solvent removed under reduced pressure (50 mg, 23%yield). The crude product (50 mg, 0.12 mmol) was dissolved in 200 μLDMSO and treated with piperidine (36 μL, 0.36 mmol). The reactionmixture was heated to 100° C. for 15 hr. The reaction mixture wascooled, diluted with H₂O, and extracted 3× with 50% EtOAc:hexanes. Theorganic layers were combined and evaporated under reduced pressure. Thecrude product was purified by preparative thin layer chromatography(silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F₂₆₄) elutingwith EtOAc:hexane (2:3) to give 27 mg (54% yield) of the title compoundas a white solid: ¹H NMR (CDCl₃, 400 MHz) 7.22-7.15 (m, 1H), 7.15-7.11(m, 1H), 6.98-6.91 (m, 1H), 5.55 (s, 2H), 4.10 (q, 2H, J=7.1 Hz), 3.30(s, 3H), 3.08-3.01 (m, 4H), 1.53-1.47 (m, 6H), 1.30 (t, 3H, J=7.1 Hz);MS (ESP+) m/e 420 (MH⁺); TLC (EtOAc:hexanes/1:2) R_(f)=0.24.

EXAMPLE 397-(2-Chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3-propyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 38to give 22 mg (11% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.13-7.10 (m, 1H), 6.97-6.90 (m, 1H), 5.53 (s, 2H),4.02-3.96 (m, 2H), 3.28 (s, 3H), 3.06-3.01 (m, 4H), 1.80-1.69 (m, 2H),1.51-1.46 (m, 6H), 0.91 (t, 3H, J=7.6 Hz); MS (ESP+) m/e 434 (MH⁺); TLC(EtOAc:hexanes/1:2) R_(f)=0.35.

EXAMPLE 407-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 38to give 22 mg (11% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.21-7.14 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.90 (m, 1H), 5.55 (s, 2H),5.17-5.05 (m, 1H), 3.27 (s, 3H), 3.06-3.01 (m, 4H), 1.53 (d, 6H, J=6.9),1.50-1.46 (m, 6H); MS (ESP+) m/e 434 (MH⁺); TLC (EtOAc:hexanes/1:2)R_(f)=0.39.

EXAMPLE 413-Benzyl-7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 38to give 11 mg (24% yield) of a clear oil: ¹H NMR (CDCl₃, 400 MHz)7.51-7.46 (m, 2H), 7.31-7.10 (m, 5H), 6.97-6.91 (m, 1H), 5.53 (s, 2H),5.20 (s, 2H), 3.27 (s, 3H), 3.11-3.05 (m, 4H), 1.54-1.46 (m, 6H); MS(ESP+) m/e 482 (MH⁺); TLC (EtOAc:hexanes/1:2) R_(f)=0.27.

EXAMPLE 427-(2-Chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-3-isopropyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione(67 mg, 0.17 mmol) and K₂CO₃ (239 mg, 1.7 mmol) in 1.7 mL DMF wastreated with isopropyl iodide (85 μL, 0.86 mmol). The reaction wasstirred at room temperature for 15 hr. The reaction mixture was filteredthrough a silica plug and rinsed with EtOAc. The solvent was removedunder reduced pressure and the crude product was purified by preparativethin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cmsilica gel 60 F₂₆₄) eluting with EtOAc:hexane (1:3) to give 46 mg (63%yield) of8-bromo-7-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione.A solution of this intermediate (45 mg, 0.11 mmol) in 110 μL aqueoussodium carbonate (2 M), 270 μL toluene, and 45 μL ethanol was treatedwith 3-chlorophenylboronic acid (18 mg, 0.12 mmol),tetrakis(triphenylphosphine)palladium(0) (3.6 mg, 0.0032 mmol), andlithium chloride (catalytic). The reaction mixture was heated to 100° C.in a sealed vial and stirred overnight. The reaction mixture was cooled,filtered through a silica plug, and rinsed with 50% EtOAc:hexanes. Thesolvent was removed under reduced pressure and the crude product waspurified by preparative thin layer chromatography (silica gel, 1 mmplate, EM Science 20×20 cm silica gel 60 h64) eluting with ether:hexane(1:1) to give 38 mg (77% yield) of the title compound as a white solid:¹H NMR (CDCl₃, 400 MHz) 7.41-7.37 (m, 1H), 7.37-7.22 (m, 3H), 7.13-7.06(m, 1H), 7.05-7.00 (m, 1H), 6.82-6.74 (m, 1H), 5.86 (s, 2H), 5.25-5.13(m, 1H), 3.35 (s, 3H), 1.58 (d, 6H, J=7); MS (ESP+) m/e 461 (MH⁺); TLC(ether:hexanes/1:1) R_(f)=0.37.

EXAMPLE 438-Bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-bromotheophylline (10 g, 39 mmol) in 30 mL water wastreated with potassium carbonate (2.6 g, 48 mmol). The reaction mixturewas refluxed until dissolved. Ethanol (30 mL) was added to the hotreaction mixture and the resulting potassium salt was filtered, washedwith acetone, and dried in a 100° C. vacuum oven. A solution of2-chloro-6-fluorobenzyl bromide (5.3 g, 24 mmol) in 10 mL DMSO wastreated with the solid potassium salt The reaction mixture was heated to100° C. for 1 hour and cooled. Upon addition of 5 mL water, the mixturewas collected by filtration and dried in a vacuum oven to yield a whitesolid (6.0 g, 89% yield): ¹H NMR (CDCl₃, 300 MHz) 7.37-7.21 (m, 2H),7.07-6.96 (m, 1H), 5.87 (s, 2H), 3.60 (s, 3H), 3.42 (s, 3H); MS (ESP+)m/e 402 (MH⁺).

EXAMPLE 447-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-phenyl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(100 mg, 0.25 mmol) in 260 μL aqueous sodium carbonate (2 M), 650 μLtoluene, and 110 μL ethanol was treated with commercially availablephenylboronic acid (34 mg, 0.27 mmol),tetrakis(triphenylphosphine)-palladium(0) (9 mg, 0.0075 mmol), andlithium chloride (catalytic). The reaction mixture was heated to 100° C.in a sealed vial and stirred overnight The reaction mixture was cooledand separated between water and ether. The aqueous layer was extractedwith ether (3×) and the combined organics were dried with magnesiumsulfate, filtered, and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel cartridge, Biotage, 32-63μm, 60 Å) with 50% EtOAc:hexanes as the eluent to afford 71 mg (71%yield) of the title compound as a white solid: ¹H NMR (CDCl₃, 300 MHz)7.61-7.36 (m, 5H), 7.19-7.04 (m, 2H), 6.88-6.76 (m, 1H), 5.89 (s, 2H),3.67 (s, 3H), 3.43 (s, 3H); MS (ESP+) m/e 400 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.45.

EXAMPLE 457-(2-chloro-6-fluorobenzyl)-8-(4-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 56 mg (52% yield) of a white solid: ¹H NMR (CDCl₃, 300 MHz)7.48-7.36 (m, 4H), 7.21-7.07 (m, 2H), 6.90-6.79 (m, 1H), 5.89 (s, 2H),3.66 (s, 3H), 3.44 (s, 3H); MS (AP+) m/e 433 (MH⁺).

EXAMPLE 467-(2-Chloro-6-fluorobenzyl)-8-(4-isopropylphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 74 mg (67% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.38-7.33 (d, 2H, J=8.2 Hz), 7.24-7.18 (d, 2H, J=8.2 Hz), 7.11-6.99 (m,2H), 6.79-6.72 (m, 1H), 5.80 (s, 2H), 3.60 (s, 3H), 3.36 (s, 3H),3.01-2.89 (m, 1H), 1.20 (d, 6H, J=6.9 Hz); MS (AP+) m/e 441 (MH⁺).

EXAMPLE 477-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-pyridin-3-yl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 12 mg (6% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)8.72-8.59 (m, 2H), 7.80-7.72 (m, 1H), 7.34-7.27 (m, 1H), 7.15-7.07 (m,1H), 7.07-7.02 (m, 1H), 6.84-6.74 (m, 1H), 5.88 (s, 2H), 3.61 (s, 3H),3.40 (s, 3H); MS (ESP+) m/e 400 (MH⁺).

EXAMPLE 487-(2-Chloro-6-fluorobenzyl)-8-(3-furyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 24 mg (12% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400MHz) 7.73-7.69 (m, 1H), 7.46-7.43 (m, 1H), 7.20-7.15 (m, 2H), 6.92-6.85(m, 1H), 6.66-6.63 (m, 1H), 5.86 (s, 2H), 3.60 (s, 3H), 3.36 (s, 3H); MS(ESP+) m/e 389 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.39.

EXAMPLE 497-(2-Chloro-6-fluorobenzyl)-8-(3,5-dichlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 20 mg (34% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.40-7.36 (m, 1H). 7.30-7.26 (m, 2H), 7.19-7.12 (m, 1H), 7.10-7.06 (m,1H), 6.87-6.81 (m, 1H), 5.91 (s, 2H), 3.61 (s, 3H), 3.42 (s, 3H); MS(ESP+) m/e 468 (MH⁺).

EXAMPLE 507-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-(3-methylphenyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 73 mg (71% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.31-7.19 (m, 4H), 7.13-7.06 (m, 1H), 7.06-7.02 (m, 1H), 6.82-6.75 (m,1H), 5.85 (s, 2H), 3.63 (s, 3H), 3.40 (s, 3H), 2.33 (s, 3H); MS (ESP+)m/e 413 (MH⁺); TLC (EtOAc:hexanes/2:1) R_(f)=0.66.

EXAMPLE 51 8-(3-Acetylphenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 18 mg (15% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)8.01-7.96 (m, 2H), 7.66-7.61 (m, 1H), 7.51-7.45 (m, 1H), 7.12-6.99 (m,2H), 6.80-6.73 (m, 1H), 5.88 (s, 2H), 3.63 (s, 3H), 3.41 (s, 3H), 2.56(s, 3H); MS (ESP+) m/e 441 (MH⁺); TLC (EtOAc:hexanes/2:1) R_(f)=0.55.

EXAMPLE 527-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-(2-naphthyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 64 mg (57% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)8.01-7.94 (m, 1H), 7.86-7.80 (m, 3H), 7.59-7.49 (m, 3H), 7.10-6.96 (m,2H), 6.74-6.65 (m, 1H). 5.94 (s, 2H), 3.66 (s, 3H), 3.41 (s, 3H); MS(ESP+) m/e 449 (MH⁺); TLC (EtOAc:hexanes/2:1) R_(f)=0.61.

EXAMPLE 537-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-(3-nitrophenyl)-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 40 mg (36% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400MHz) 8.31-8.21 (m, 2H), 7.82-7.75 (m, 1H), 7.60-7.53 (m, 1H), 7.15-7.00(m, 2H), 6.82-6.73 (m, 1H), 5.93 (s, 2H), 3.62 (s, 3H), 3.42 (s, 3H); MS(ESP+) m/e 444 (MH⁺); TLC (EtOAc:hexanes/2:1) R_(f)=0.55.

EXAMPLE 548-(1,3-Benzodioxol-5-yl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 10 mg (8% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400 MHz)7.17-7.05 (m, 2H), 6.99-6.91 (m, 2H), 6.87-6.77 (m, 2H), 5.99 (s, 2H),5.83 (s, 2H), 3.61 (s, 3H), 3.38 (s, 3H); MS (ESP+) m/e 443 (MH⁺); TLC(EtOAc:hexanes/2:1) R_(f)=0.63.

EXAMPLE 558-(3-Aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44to give 530 mg (51% yield) of a pale yellow solid: ¹H NMR (CDCl₃, 400MHz) 7.15-7.02 (m, 3H), 6.84-6.77 (m, 2H), 6.75-6.73 (m, 1H), 6.71-6.66(m, 1H), 5.83 (s, 2H), 3.72 (s, 2H), 3.61 (s, 3H), 3.37 (s, 3H); MS(ESP+) m/e 414 (MH⁺); TLC (EtOAc:hexanes/2:1) R_(f)=0.22.

EXAMPLE 56 tert-Butyl2-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]-1H-pyrrole-1-carboxylate

The title compound was prepared according to the procedure of Example 44to give 19 mg (16% yield) of a white solid: ¹H NMR (CDCl₃, 400 MHz)7.26-7.23 (m, 1H), 7.12-7.05 (m, 1H), 7.04-7.00 (m, 1H), 6.81-6.74 (m,1H), 6.04-6.01 (m, 1H), 6.01-5.98 (m, 1H), 5.80 (s, 2H), 3.60 (s, 3H),3.44 (s, 3H), 1.44 (s, 9H); MS (ESP+) m/e 488 (MH⁺); TLC(EtOAc:hexanes/2:1) R_(f)=0.75.

EXAMPLE 577-(2-Chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44(8 mg, 7% yield): ¹H NMR (CDCl₃, 400 MHz) 7.40-7.35 (m, 2H), 7.31-7.26(m, 2H), 7.14-7.07 (m, 1H), 7.05-7.02 (m, 1H), 6.82-6.75 (m, 1H), 5.86(s, 2H), 3.60 (s, 3H), 3.39 (s, 3H); MS (ESP+) m/e 433 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.71.

EXAMPLE 587-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-[3-(trifluoromethyl)phenyl]-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44(53 mg, 45% yield): ¹H NMR (CDCl₃, 400 MHz) 7.65-7.58 (m, 3H), 7.51-7.45(m, 1H), 7.10-7.03 (m, 1H), 7.01-6.97 (m, 1H), 6.76-6.70 (m, 1H), 5.87(s, 2H), 3.60 (s, 3H), 3.39 (s, 3H); MS (ESP+) m/e 467 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.69.

EXAMPLE 597-(2-Chloro-6-fluorobenzyl)-8-(3-methoxyphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The title compound was prepared according to the procedure of Example 44(13 mg, 12% yield): ¹H NMR (CDCl₃, 400 MHz) 7.29-7.24 (m, 1H), 7.13-6.98(m, 3H), 6.96-6.91 (m, 2H), 6.81-6.75 (m, 1H), 5.82 (s, 2H), 3.75 (s,3H), 3.61 (s, 3H), 3.37 (s, 3H); MS (ESP+) m/e 429 (MH⁺); TLC(EtOAc:hexanes/1:1) R_(f)=0.51.

EXAMPLE 607-(2-Chloro-6-fluorobenzyl)-8-cyclopentyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 8-cyclopentyl-1,3-dimethylxanthine (100 mg, 0.40 mmol) andK₂CO₃ (80 mg, 0.58 mmol) was treated with 2-chloro-6-fluorobenzylbromide (142 mg, 0.64 mmol) dissolved in 400 μL DMF. The reactionmixture was sealed and heated to 60° C. for 24 hrs. The reaction mixturewas cooled and purified by preparative thin layer chromatography (silicagel, 1 mm plate, EM Science 20×20 cm silica gel 60 F₂₆₄) eluting withEtOAc:hexane (1:1) to give 23 mg (14% yield) of the title compound as awhite solid: ¹H NMR (CDCl₃, 400 MHz) 7.29-7.11 (m, 2H), 7.01-6.85 (m,1H), 5.86 (s, 2H), 3.54 (s, 3H), 3.38 (s, 3H); 3.02-2.81 (m, 1H),1.83-1.43 (m, 8H); MS (ESP+) m/e 391 (MH⁺); TLC(EtOAc:hexanes/1:1)R_(f)=0.58.

EXAMPLE 617-(2-Chloro-6-fluorobenzyl)-8-cyclohexyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of 5,6-diamino-1,3-dimethyluracil hydrate (1 g, 5.9 mmol) and2,3-dichloro-5,6-dicyanoquinone (1.34 g, 5.9 mmol) in 15 mL acetonitrilewas treated with cyclohexane carboxaldehyde (0.71 mL, 5.9 mmol). Thereaction mixture was stirred at room temperature for 15 hrs and thentreated with 0.5 M NaOH (24 mL) and stirred an additional 48 hrs. Theprecipitate was filtered and dried (345 mg, 22% yield). A solution ofthe precipitate (200 mg, 0.76 mmol) and K₂CO₃ (105 mg, 0.76 mmol) wastreated with 2-chloro-6-fluorobenzyl bromide (187 mg, 0.84 mmol)dissolved in 1 mL DMF. The reaction mixture was heated in a sealed vialto 60° C. for 24 hrs. An additional 28 mg K₂CO₃ and 51 mg2-chloro-6-fluorobenzyl bromide was added to the reaction and thereaction mixture was heated in a sealed vial to 60° C. for another 24hrs. The reaction mixture was cooled and, upon addition of water, theresulting precipitate was collected by filtration. The crude product waspurified by flash chromatography (silica gel cartridge, Biotage, 32-63□m, 60 Å) with 33% EtOAc:hexanes as the eluent to afford 134 mg (44%yield) of the title compound as a tan solid: ¹H NMR (CDCl₃, 400 MHz)7.30-7.20 (m, 2H), 7.01-6.94 (m, 1H), 5.90 (s, 2H), 3.60 (s, 3H), 3.40(s, 3H), 2.64-2.53 (m, 1H), 1.79-1.53 (m, 5H), 1.42-1.05 (m, 5H); MS(ESP+) m/e 405 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.59.

EXAMPLE 627-(2-Chloro-6-fluorobenzyl)-8-(3-hydroxyphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(88 mg, 0.21 mmol) in 310 μL water was treated with concentrated HCl andthen sodium nitrite (19 mg, 0.23 mmol) dissolved in ˜300 μL water. Thereaction mixture was stirred at 0° C. for 30 min and then heated to 100°C. for 15 min. The reaction mixture was cooled, dried under reducedpressure, and purified by preparative thin layer chromatography (silicagel, 1 mm plate, EM Science 20×20 cm silica gel 60 F₂₆₄) eluting withEtOAc:hexane (2:1) to give 37 mg (43% yield) of the title compound as apale orange solid: ¹H NMR (CDCl₃, 400 MHz) 7.22-7.16 (m, 1H), 7.12-7.01(m, 2H), 6.96-6.91 (m, 2H), 6.86-6.81 (m, 1H), 6.80-6.74 (m, 1H), 5.82(s, 2H), 3.60 (s, 3H), 3.37 (s, 3H); MS (ESP+) m/e 415 (MH⁺); TLC(EtOAc:hexanes/2:1) R_(f)=0.41.

EXAMPLE 637-(2-Chloro-6-fluorobenzyl)-8-(3-iodophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3.7-dihydro-1H-purine-2,6-dione(100 mg, 0.24 mmol) in 600 μL 1 N HCl was cooled to 0° C. and slowlytreated with sodium nitrite (27 mg, 0.32 mmol) dissolved in ˜700 μLwater. The reaction mixture was stirred at 0° C.-5° C. for 30 min andthen Kl (100 mg, 0.60 mmol) was added in small portions. The reactionmixture was then heated to 80° C. for 1 hr. cooled, and extracted withEtOAc. The EtOAc layers were combined, dried over Na₂SO₄, and driedunder reduced pressure. The crude product was purified by preparativethin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cmsilica gel 60 F₂₆₄) eluting with EtOAc:hexane (1:1) to give 40 mg (32%yield) of the title compound as an off-white solid: ¹H NMR (CDCl₃, 400MHz) 7.74-7.67 (m, 2H), 7.40-7.36 (m, 1H), 7.15-7.02 (m, 3H), 6.82-6.75(m, 1H), 5.85 (s, 2H), 3.60 (s, 3H), 3.39 (s, 3H); MS (ESP+) m/e 525(MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.54.

EXAMPLE 64N-{3-[7-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]phenyl}acetamide

A solution of8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(25 mg, 0.06 mmol) in 255 μL CH₂Cl₂ was treated with acetic anhydride(6.6 μL, 0.07 mmol). The reaction was stirred for 1.5 hr and then blowndry under nitrogen. The crude product was purified by preparative thinlayer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silicagel 60 F₂₆₄) eluting with EtOAc:hexane (3:1) to give 4 mg (15% yield) ofthe title compound as a clear oil: ¹H NMR (CDCl₃, 400 MHz) 7.67-7.61 (m,2H), 7.36-7.26 (m, 2H), 7.21-7.15 (m, 1H), 7.13-7.01 (m, 2H), 6.84-6.75(m, 1H), 5.86 (s, 2H), 3.62 (s, 3H), 3.38 (s, 3H), 2.97 (s, 3H); MS(ESP+) m/e 456 (MH⁺); TLC (EtOAc:hexanes/3:1) R_(f)=0.11.

EXAMPLE 65N-{3-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]phenyl}-2,2,2-trifluoroacetamide

A solution of8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(20 mg, 0.05 mmol) in 213 μL CH₂Cl₂ was treated with trifluoroaceticanhydride (7.8 μL, 0.06 mmol). The reaction was stirred for 1.5 hr andthen blown dry under nitrogen. The crude product was purified bypreparative thin layer chromatography (silica gel, 1 mm plate, EMScience 20×20 cm silica gel 60 F₂₆₄) eluting with EtOAc:hexane (2:1) togive 18 mg (72% yield) of the title compound as a white solid: ¹H NMR(CDCl₃, 400 MHz) 8.16 (s, 1H), 7.74-7.65 (m, 2H), 7.41 (t, 1H, J=8.1Hz), 7.35-7.30 (m, 1H), 7.14-7.01 (m, 2H), 6.83-6.75 (m, 1H), 5.88 (s,2H), 3.62 (s, 3H), 3.39 (s, 3H), 2.97 (s, 3H); MS (ESP+) m/e 510 (MH⁺);TLC (EtOAc:hexanes/3:1) R_(f)=0.68.

EXAMPLE 66[7-(2-Chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]aceticacid

A solution of tert-butyl[7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate(24 mg, 0.046 mmol) in 230 μL CH₂Cl₂ was treated with 230 μL TFA. Thereaction was stirred at room temperature for 1 hr and then the solventwas removed by reduced pressure. The crude product was filtered througha silica plug and rinsed with 20% MeOH/EtOAc. The solvent was removedaffording the title compound (19 mg, 90% yield) as a white solid: ¹H NMR(CDCl₃, 400 MHz) 7.22-7.16 (m, 1H), 7.14-7.10 (m, 1H), 6.98-6.91 (m,1H), 5.51 (s, 2H), 4.80 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 3.11-3.01 (m,4H), 1.54-1.41 (m, 6H), 1.12 (t, 3H, J=7.0 Hz); MS (ESP+) m/e 464 (MH⁺).

EXAMPLE 673-[7-(2-Chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]propanoicacid

A solution of methyl3-[7-(2-chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]propanoate(9 mg, 0.018 mmol) in 150 μTHF and 50 μL H₂O was treated with 18 μL 1 NLiOH. The reaction mixture was stirred at room temperature overnight andthen treated with 18 μL 1 N acetic acid. The product was extracted intoEtOAc and then the solvent was removed by reduced pressure. The crudeproduct was purified by preparative thin layer chromatography (silicagel, 1 mm plate, EM Science 20×20 cm silica gel 60 F₂₆₄) eluting with100% EtOAc to give 3 mg (13% yield) of the title compound as a clearoil: ¹H NMR (CDCl₃, 400 MHz) 7.23-7.17 (m, 1H), 7.15-7.12 (m, 1H),6.99-6.94 (m, 1H), 5.52 (s, 2H), 5.16-5.07 (m, 1H), 4.21 (t, 2H, J=6.9Hz), 3.14-3.04 (m, 4H), 2.66 (t, 2H, J=6.9 Hz), 1.56-1.51 (m, 12H); MS(ESP+) m/e 492 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.61.

EXAMPLE 69 Ethyl1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylate

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(6.0 g, 0.015 mol) in 30 mL of DMSO was treated with (+/−)-ethylpiperidine-3-carboxylate (11.7 g, 0.075 mol) and heated at 100° C. for15 h. The reaction was cooled to room temperature and treated with H₂Oand CH₂Cl₂. The layers were separated, and the aqueous layer wasextracted with CH₂Cl₂ (2×). The combined organic layers were washed withH₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, Merck 20×20 cmsilica gel 60 F₂₅₄) eluting with 7:3/hexanes:EtOAc to give 6.33 g (88%yield) of the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 7.20 (dt, 2H,J=8.1, 5.7), 7.14 (t, 1H, J=7.6), 6.98-6.90 (m, 1H), 5.57 (AB quartet,2H, J=15.7, 5.7), 4.18-4.00 (m, 2H), 3.51 (s, 3H), 3.42 (dd, 1H, J=12.6,4.0), 3.30 (s, 3H), 3.18 (br d, 1H), 3.06 (dd, 1H, J=12.4, 10.0),2.91-2.83 (m, 1H), 2.52-2.41 (m, 1H), 2.03-1.92 (m, 1H), 1.75-1.66 (m,1H), 1.63-1.40 (m, 2H), 1.21 (t, 3H, J=7.1); LRMS (ESI) m/z 478 (M+H⁺);TLC (hexanes:EtOAc/7:3) R_(f)=0.20.

EXAMPLE 701-[7-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylicacid

A solution of ethyl1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylate(5.0 g, 10.5 mmol) in 75 mL THF and 25 mL H₂O at room temperature wastreated with solid LiOH (1.8 g, 43.9 mmol). After stirring overnight theTHF was removed under reduced pressure, and the residue was diluted withH₂O. The aqueous layer was acidified to pH 4, and the aqueous layer wasextracted with CH₂Cl₂. The combined extracts were concentrated underreduced pressure to give 4.9 g (>99% yield) of the title compound: ¹HNMR (CDCl₃, 400 MHz) δ7.18 (dt, 2H, J=8.1, 5.7), 7.14 (t, 1H, J=7.6),6.98-6.90 (m, 1H), 5.57 (AB quartet, 2H, J=15.7, 5.7), 3.51 (s, 3H),3.42 (dd, 1H, J=12.6, 4.0), 3.30 (s, 3H), 3.20-3.05 (m, 2 H), 2.94-2.83(m, 1H), 2.59-2.47 (m, 1H), 2.03-1.93 (m, 1H), 1.75-1.40 (m, 3H); LRMS(ESI) m/z 450 (M+H⁺); TLC (hexanes:EtOAc/1:1) R_(f)=0.10.

EXAMPLE 711-[7-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]-N-(2-hydroxyethyl)piperidine-3-carboxamide

A solution of1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylicacid (30 mg, 0.066 mmol) in 1.0 mL of CH₂Cl₂ at room temperature wastreated with polystyrene-carbodiimide (1.15 mmol/g, 104 mg, 0.12 mmol)and stirred for 30 min. The reaction mixture was treated with2-aminoethanol (0.004 mL, 0.066 mmol), allowed to rotate overnight,filtered, and concentrated in vacuo. The crude product was purified bypreparative TLC chromatography eluting with 5:5:1/hexanes:EtOAc:MeOH togive 11 mg (33% yield) of the title compound: ¹H NMR (CDCl₃, 400 MHz) δ7.26-7.14 (m, 2H), 7.00-6.93 (m, 1H), 6.17 (br s), 5.58 (d, 2H, J=1.5),3.70 (t, 2H, J=5.1), 3.51 (s, 3H), 3.47-3.36 (m, 3H), 3.31 (s, 3H), 3.23(br d, 1H, J=12.3), 3.12 (dd, 1H, J=12.8, 10.3), 2.97-2.88 (m, 1H),2.42-2.32 (m, 1H), 1.94-1.86 (m, 1H), 1.82-1.45 (m, 4H); LRMS (ESI) m/z493 (M+H⁺); TLC (hexanes:EtOAc:MeOH/5:5:1) R_(f)=0.12.

EXAMPLES 72-143 (Table 1) Were Prepared as in Example 71

TABLE 1 Ex # Structure MH⁺ HPLC purity t_(r) 72

502 100 3.8 73

489 97 3.9 74

491 79 4.0 75

491 60 4.1 76

502 90 3.7 77

503 100 4.1 78

505 100 4.2 79

505 80 4.1 80

505 98 4.2 81

507 100 3.9 82

517 98 4.2 83

519 100 4.3 84

519 100 4.3 85

505 40 4.2 86

516 100 3.8 87

517 100 4.3 88

519 100 3.9 89

519 100 4.4 90

519 70 4.4 91

519 40 4.4 92

519 72 4.3 93

521 100 4.0 94

521 80 4.1 95

531 100 4.4 96

532 100 2.8 97

533 68 5.5 98

519 100 4.3 99

519 100 4.4 100

519 100 4.3 101

521 90 3.9 102

521 100 4.0 103

529 100 4.0 104

531 2 4.1 105

531 100 4.4 106

535 100 4.1 107

535 100 4.1 108

535 100 4.1 109

545 100 4.1 110

546 80 2.9 111

533 99 4.5 112

533 40 4.5 113

533 93 4.5 114

535 100 4.2 115

545 100 4.5 116

546 83 3.7 117

546 100 2.9 118

546 100 2.8 119

547 100 4.6 120

549 97 4.3 121

559 93 4.6 122

560 90 2.9 123

561 100 4.7 124

560 80 3.0 125

477 100 3.9 126

501 100 5.2 127

501 50 5.2 128

503 80 4.1 129

505 98 4.2 130

505 0 4.2 131

521 100 3.9 132

521 97 3.7 133

533 100 3.8 134

561 100 4.7 135

562 89 2.9 136

562 100 3.7 137

560 100 3.7 138

560 100 3.7 139

560 100 3.7 140

463 100 3.8 141

477 100 3.9 142

507 100 3.9 143

507 100 3.7

EXAMPLE 1447-(2-Chloro-6-fluorobenzyl)-1,3-dimethyl-8-pyrrolidin-1-yl-3,7-dihydro-1H-purine-2,6-dione

A solution of8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione(50 mg, 0.12 mmol) in 300 μL DMSO was treated with pyrrolidine (55 μL,0.55 mmol) and heated at 130° C. for 15 h. The reaction was cooled to25° C. and treated with 1 mL H₂O. After centrifugation for 1 h theliquid was decanted, and the process was repeated. The reaction wastreated with 1 mL toluene and concentrated under reduced pressure. Theresidue was treated with 2 mL CH₂Cl₂ followed by isocyanate scavengerresin (500 mg, 0.58 mmol, 1.16 mmol/g). The reaction was filtered afteragitating for 30 min, and the filtrate was concentrated under reducedpressure to give 48 mg (>99% yield) of the title compound: ¹H NMR(CDCl₃, 300 MHz) 7.27-7.18 (m, 2H), 7.02-6.91 (m, 1H), 5.73 (s, 2H),3.59-3.48 (m, 7H), 3.35 (s, 3H), 1.98-1.87 (m, 4H); MS (ESP+) m/e 392(MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.24.

EXAMPLES 145-721 (FIG. 1) Were Prepared According to the MethodDescribed in Example 144

Physical characterizing data is provided for each in MH+ and HPLCpurity.

EXAMPLE 722 Assay for LXRβ Activity

A modified polyhistidine tag (MKKGHHHHHHG) (SEQ ID No. 1) was fused inframe to the human LXRβ ligand binding domain (amino acids 185-461 ofGenbank accession number U07132) and subeloned into the expressionvector pRSETa (Invitrogen) under the control of an IPTG inducible T7promoter. The human LXRβ ligand binding domain was expressed in E. colistrain BL21 (DE3). Ten-liter fermentation batches were grown in Rich PO₄media with 0.1 mg/mL Ampicillin at 25° C. for 12 hours, cooled to 9° C.and held at that temperature for 36 hours to a density of OD600=14. Atthis cell density, 0.25 mM IPTG was added and induction proceeded for 24hours at 9° C., to a final OD600=16. Cells were harvested bycentrifugation (20 minutes, 3500 g, 4° C.), and concentrated cellslurries were stored in PBS at −80° C.

Typically 25-50 g of cell paste is resuspended in 250-500 mL TBS, pH 8.0(25 mM Tris, 150 mM NaCl). Cells are lysed by passing 3 times through anAPV Rannie MINI-lab homogenizer, and cell debris is removed bycentrifugation (30 minutes, 20,000 g, 4° C.). The cleared supernatant isfiltered through coarse pre-filters, and TBS, pH 8.0, containing 500 mMimidazole is added to obtain a final imidazole concentration of 50 mM.This lysate is loaded onto a column (XK-26, 10 cm) packed with Sepharose[Ni++ charged] Chelation resin (available from Pharmacia) andpre-equilibrated with TBS pH 8.0/50 mM imidazole. After washing tobaseline absorbance with equilibration buffer, the column is washed withapproximately one column volume of TBS pH −8.0 containing 95 mMimidazole. LXRβLBD(185-461) is eluted with a gradient from 50 to 500 mMimidazole. Column peak fractions are pooled immediately and diluted 5fold with 25 mM Tris pH 8.0, containing 5% 1,2-propanediol, 0.5 mM EDTAand 5 mM DTT. The diluted protein sample is then loaded onto a column(XK-16, 10 cm) packed with Poros HQ resin (anion exchange). Afterwashing to baseline absorbance with the dilution buffer the protein iseluted with a gradient from 50-500 mM NaCl. Peak fractions are pooledand concentrated using Centri-prep 10K (Amicon) filter devices andsubjected to size exclusion, using a column (XK-26, 90 cm) packed withSuperdex-75 resin (Pharmacia) pre-equilibrated with TBS, pH 8.0,containing 5% 1,2-propanediol, 0.5 mM EDTA and 5 mM DTT.

LXRβ protein was diluted to approximately 10 microM in PBS and five-foldmolar excess of NHS-LC-Biotin (Pierce) was added in a minimal volume ofPBS. This solution was incubated with gentle mixing for 30 minutes atambient room temperature. The biotinylation modification reaction wasstopped by the addition of 2000× molar excess of Tris-HCl, pH 8. Themodified LXRβ protein was dialyzed against 4 buffer changes, each of atleast 50 volumes, PBS containing 5 mM DTT, 2 mM EDTA and 2% sucrose. Thebiotinylated LXRβ protein was subjected to mass spectrometric analysisto reveal the extent of modification by the biotinylation reagent. Ingeneral, approximately 95% of the protein had at least a single site ofbiotinylation; and the overall extent of biotinylation followed a normaldistribution of multiple sites, ranging from one to nine.

The biotinylated protein was incubated for 20-25 minutes at aconcentration of 25 nM in assay buffer (50 mM KCl, 50 mM Tris-pH8, 0.1mg/ml FAF-BSA, 10 mM DTT) with equimolar amounts ofstreptavidin-AlloPhycoCyanin (APC, Molecular Probes). At the same time,the biotinylated peptide comprising amino acids 675-699 of SRC-1(CPSSHSSLTERHKILHRLLQEGSPS-CONH2) (SEQ ID No. 2) at a concentration of20 nM was incubated in assay buffer with a ½ molar amount ofstreptavidin-labelled Europium (Wallac) for 20-25 minutes. After theinitial incubations are completed, a 10 molar excess (250 nM) of coldbiotin was added to each of the solutions to block the unattachedstreptavidin reagents. After 20 min at room temp, the solutions weremixed yielding a concentration of 10 nM for the dye-labelled LXRβprotein and SRC-1 peptide. Representative data is shown in Tables 2A and2B. Percentage control is relative to 24(S),25-epoxycholesterol.

In this assay 1 μM 24(S),25-epoxycholesterol gave a reading of 20000fluorescence units over a background reading of 10000 fluorescenceunits.

EXAMPLE 723 Assay for LXRα Activity

The assay for LXRα was run according to the procedures of Example 1,above using his-tagged LXRα ligand binding domain (amino acids 183-447of Genbank accession number U22662, with the 14^(th) amino acidcorrected to A from R). Representative data is shown in Tables 2A and2B. Percentage control is relative to 24(S),25-epoxycholesterol.

In this assay 1 μM 24(S),25-epoxycholesterol gave a reading of 20000fluorescence units over a background reading of 10000 fluorescenceunits.

EXAMPLE 724 Assay for ABC1 Expression in Macrophages

RAW 264.7 cells, obtained from ATCC, were grown in Dulbecco's ModifiedEagle Media (DMEM, GIBCO) supplemented with 10% fetal bovine serum (FBS,Irvine Scientific), 2 mM glutamine (Irvine Scientific), 100 Upenicillin/ml and 100 mg streptomycin/ml (Irvine Scientific). Cells werepassaged routinely at 3-4 day intervals at a plating density of 1:3.

To assess the effects of test compounds on ABC1 expression, the cellswere passaged into CS media (DMEM/F12 media without phenol redsupplemented with 10% charcoal/dextran-treated FBS, 2 mM glutamine, 100U penicillin/ml and 100 mg streptomycin/ml and 100 mM mevalonic acidlactone). Two days later, the media was replaced with fresh CS mediacontaining 10 μM of the test compound. After 24 hours, the media wasremoved and replaced with fresh CS media containing fresh drug. After 24more hours, the media was aspirated and the cells lysed in Trizolreagent (GIBCO). RNA was then extracted according to manufacturer'sinstructions. The RNA was quantitated following RNAse-free DNAsetreatment by using the Ribogreen System (Molecular Probes), and thendiluted to 10 ng/microL.

ABC1 expression was determined by quantitative PCR. TaqMan reactionswere performed using the standard conditions on the ABI7700; 5.5 mMMgCl2, 1× TaqMan Buffer A, 300 microM each dNTP, 20 U RNAse inhibitor,12.5 U MuLV RT; ase, 300 nM of each primer, 200 nM TaqMan probe, 1.25 UAmpliTaq Gold, and 50 ng RNA in a 50 uL volume. The reaction conditionswere 48° C. for 30 minutes, 95° C. for 10 minutes, and 40 cycles of 94°C. for 15 seconds/60° C. for 1 minute. The sequence of the primers andprobe for mouse ABC1 (X75926) were: forward primer:AAGGGTTTCTTTGCTCAGATTGTC (SEQ ID No. 3); reverse primer:TGCCAAAGGGTGGCACA (SEQ ID No. 4); probe oligo: CCAGCTGTCTTTGTTTGCATTGCCC(SEQ ID No. 5). Results were analyzed on the ABI7700 using SequenceDetector v1.6 software provided with the machine. ABC1 expression wascalculated as fold induction in test compound-treated cells relative tovehicle-treated cells.

1. A compound of formula (I):

wherein: n is 1, 2, 3, 4, 5; each R¹ is the same or different and is independently selected from the group consisting of halo, alkyl, and nitro; R² is a substituent selected from the group consisting of formulas vi and vii:

each Ring A and Ring B is the same or different and is independently selected from the group consisting of C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay and Het; Ay is aryl; Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl; a and b are each the same or different and are independently 0 or 1; p is 0, 1 or 2; q is 0, 1, 2or 3; each R⁵ is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶, —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸CO₂R⁹, nitro and cyano; g is 0, 1 or 2; R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl, —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy; R⁶ and R⁷ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹; R⁸ is alkylene or alkenylene; R⁹ and R¹⁰ are each the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl and alkynyl; and R¹² is selected from the group consisting of H, alkyl, alkenyl, and alkynyl, or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein n is 1 or
 2. 3. The compound according to claim 1, wherein each R¹ is the same or different and is independently selected from the group consisting of halo and alkyl.
 4. The compound according to claim 1, wherein each R¹ is the same or different and is halo.
 5. The compound according to claim 1, wherein R² is a substituent of formula (vi-a):

where Y is N or CH.
 6. The compound according to claim 1, wherein R² is a substituent of formula (vii-a):


7. A compound of formula (I-A):

wherein: R¹⁵ is selected from the group consisting of

R² is a substituent selected from the group consisting of:

q is 0, 1, 2 or 3; each R¹¹ is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶, —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O_(g)R⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R⁸—C(O)Ay, —R⁸—C(O)Het, —R⁸CO₂R⁹, —R⁸C(O)N(R⁹)Ay, —CH-(Ay)₂, —CH-(Het)₂, nitro and cyano; g is 0, 1 or 2; Ay is aryl; Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl; R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀ cycloalkyl, —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy, wherein when R² is

then R³ and R⁴ are not both methyl; R⁶ and R⁷ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹; R⁸ is alkylene or alkenylene; and R⁹ and R¹⁰ are each the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof.
 8. The compound according to claim 7 wherein R² is


9. The compound according to claim 7, wherein q is 0, 1 or
 2. 10. The compound according to claim 7, wherein each R¹¹ is the same or different and is independently selected from the group consisting of halo, alkyl, —OH, —OR⁶, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —C(O)₂R⁸Ay, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸CO₂R⁹, R⁸C(O)N(R⁹)Ay and nitro.
 11. The compound according to claim 7, wherein R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, alkyl (trifluoroethyl), C₃₋₁₀cycloalkyl, Ay, R⁸-Ay, —R⁸OH, —R⁸Oalkyl, —R⁸Salkyl, —R⁸CO₂H, —R⁸CO₂alkyl, R⁸-O-Ay, —R⁸C(O)NH₂, —R⁸-cycloalkyl


12. A compound of formula (I-A):

wherein: R¹⁵ is selected from the group consisting of

R² is a substituent of formula (v-a):

p is 0, 1 or 2; q is 0, 1, 2 or 3; each R⁵ is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, —OR⁶, —OC(O)R⁶, —OR⁸C(O)R⁶, —S(O)_(g)R⁶, —C═0, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —NR⁶R⁷, —N(R⁶)C(O)R⁶, —R⁸OR⁶, —R⁸NR⁶R⁷, —R⁸C(O)R⁶, —R^(8CO) ₂R⁹, nitro and cyano; g is 0, 1 or 2; Ay is aryl; Het is a 3-10 membered heterocycle or a 5-10 membered heteroaryl; R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl, Ay, Het, —R⁸—C₃₋₁₀cycloalkyl, —R⁸-Ay, —R⁸-Het, —R⁸CO₂R⁹, —R⁸C(O)NR⁹R¹⁰, —R⁸OR⁹, —R⁸SR⁹ and —R⁸OAy; R⁶ and R⁷ are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, —R⁸OR⁹, —R⁸SR⁹, —R⁸—NR⁹R¹⁰, —R⁸—CN, —R⁸—CO₂R⁹; R⁸ is alkylene or alkenylene; and R⁹ and R¹⁰ are each the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl and alkynyl; or a pharmaceutically acceptable salt thereof.
 13. The compound according to claim 12, wherein p is
 0. 14. The compound according to claim 12, wherein q is 0, 1 or
 2. 15. The compound according to claim 12, wherein each R⁵ is the same or different and is independently selected from the group consisting of halo, alkyl, —OR⁶, —C═O, —C(O)R⁶, —C(O)NR⁶R⁷, —CO₂R⁹, —N(R⁶)C(O)R⁶, —R⁸OR⁶ and nitro.
 16. The compound according to claim 12, wherein R³ and R⁴ are the same or different and are each independently selected from the group consisting of H, alkyl (trifluoroethyl), C₃₋₁₀cycloalkyl, Ay, R⁸-Ay, —R⁸OH, —R⁸Oalkyl, —R⁸Salkyl, —R⁸CO₂H, —R⁸CO₂alkyl, R⁸—O-Ay, —R⁸C(O)NH₂, —R⁸—C₃₋₁₀cycloalkyl,


17. A compound selected from the group consisting of: 7-(2-chloro-6-fluorobenzyl)-1,3-diethyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-3-ethyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-3-isopropyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-isopropyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-methoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; methyl[7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate; 7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-(2-phenoxyethyl)-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 1-butyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-(cyolopropylmethyl)-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1,3-diisopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-cyclopropyl-3-isopropyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-ethyl-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-1-propyl-3,7-dihydro-1H-purine-2,6-dione; 1-benzyl-7-(2-chloro-6-fluorobenzyl)-3-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3-propyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 3-benzyl-7-(2-chloro-6-fluorobenzyl)-1-methyl-8-piperidin-1-yl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-3-isopropyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1, 3-dimethyl-8-phenyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(4-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(3,5-dichlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-(2-naphthyl)-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(3-chlorophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-[3-(trifluoromethyl)phenyl]-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(3-methoxyphenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-cyclohexyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-(3-iodophenyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylic acid; 7-(2-chloro-6-fluorobenzyl)-8-{3-[(4-hydroxypiperidin-1-yl)carbonyl]piperidin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]-N-(4-hydroxybutyl)piperidine-3-carboxamide; 7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-8-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-[4-(3-methoxyphenyl)piperazin-1-yl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; 7-(2-chloro-6-fluorobenzyl)-8-{4-[4-chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; and pharmaceutically acceptable salts thereof.
 18. A pharmaceutical composition comprising a compound according to claim
 1. 19. The pharmaceutical composition according to claim 18 further comprising a pharmaceutically acceptable carrier or diluent. 